Influenza A virus vaccines and inhibitors

ABSTRACT

The present invention includes compositions and methods related to the structure and function of the cellular polyadenylation and specificity factor 30 (CPSF30) binding site on the surface of the influenza A non-structural protein 1 (NS1). Specifically, critical biochemical reagents, conditions for crystallization and NMR analysis, assays, and general processes are described for (i) discovering, designing, and optimizing small molecule inhibitors of influenza A (avian flu) viruses and (ii) creating attenuated influenza virus strains suitable for avian and human flu vaccine development.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 13/907,472, filed onMay 31, 2013, which is a divisional patent application of U.S. Ser. No.12/706,804, filed on Feb. 17, 2010, now U.S. Pat. No. 8,455,621, whichis a divisional of U.S. patent application Ser. No. 11/566,216, filed onDec. 2, 2006, now U.S. Pat. No. 7,709,190, which claims priority to U.S.Provisional Application Ser. No. 60/741,764, filed Dec. 2, 2005 and Ser.No. 60/852,361 filed Oct. 16, 2006. All of the foregoing applicationsare hereby incorporated by reference in their entirety.

STATEMENT OF FEDERALLY FUNDED RESEARCH

This invention was made with U.S. Government support under Contract Nos.AI-11772 awarded by the NIH. The government has certain rights in thisinvention.

TECHNICAL FIELD OF THE INVENTION

The present invention relates in general to the field of anti-viralassays and molecules, and more particularly, to compositions and methodsfor developing, isolating and characterizing novel Influenza A virusinhibitors and vaccines.

INCORPORATION-BY-REFERENCE OF MATERIALS FILED ON COMPACT DISC

The present application includes a TABLE filed electronically viaEFS-Web that includes a file named NS1A_F2F3. The table was lastmodified Dec. 1, 2006 at 4:49 PM and includes 252,952 bytes.

TABLES The patent contains table(s) that have been included at the endof the specification.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with Influenza virus.

Influenza A and B viruses cause a highly contagious respiratory diseasein humans resulting in approximately 36,000 deaths in the United Statesannually (Wright and Webster, 2001; Prevention, 2005). These annualepidemics also have a large economic impact, and cause more than 100,000hospitalizations per year in the United States alone. Influenza Aviruses, which infect a wide number of avian and mammalian species, areresponsible for the periodic widespread epidemics, or pandemics, thathave caused high mortality rates (Wright and Webster, 2001). The mostdevastating pandemic occurred in 1918, which caused an estimated 20 to40 million deaths worldwide (Reid et al., 2001). Less devastatingpandemics occurred in 1957 and 1968. Influenza B virus infectionscomprise about 20% of the yearly cases, but influenza B virus, whichappears to infect only humans, does not cause pandemics (Wright andWebster, 2001).

Influenza A and B viruses contain negative-stranded RNA genomes, whichare in the form of eight RNA segments (Lamb and Krug, 2001). Most, butnot all, of the corresponding genome RNA segments of influenza A and Bviruses encode proteins of similar functions. Here we will focus oninfluenza A virus. The three largest genome segments encode the threesubunits of the polymerase, PB1, PB2 and PA. The segment encoding PB1also encodes a small nonstructural protein, PB1-F2, which has apoptoticfunctions. The middle-sized segments encode the hemagglutinin (HA), thenucleocapsid protein (NP) and the neuraminidase (NA). HA, the majorsurface protein of the virus, binds to sialic acid-containing receptorson host cells, and is the protein against which neutralizing antibodiesare produced. NP protein molecules are bound at regular intervals alongthe entire length of each of the genomic RNAs to form ribonucleoproteins(RNPs), and also have essential functions in viral RNA replication. TheNA viral surface protein removes sialic acid from glycoproteins. One ofits major functions is to remove sialic acid during virus budding fromthe cell surface and from the HA and NA of the newly assembled virions,thereby obviating aggregation of the budding virions on the cellsurface. The seventh genomic RNA segment encodes two proteins, M1(matrix protein) and M2. The M1 protein underlies the viral lipidmembrane, and is thought to interact with the genomic RNPs and with theinner (cytoplasmic) tails of the surface proteins, e.g., HA and NA. TheM2 protein is an ion channel protein that is essential for the uncoatingof the virus. The smallest segment encodes two proteins, NS1A and NS2.The NS2 protein mediates the export of newly synthesized viral RNPs fromthe nucleus to the cytoplasm. The NS1A protein is a multi-functionalprotein not that is not incorporated into virion particles (hence thedesignation “non structural”), and is discussed below.

The primary means for controlling influenza virus epidemics has beenvaccination directed primarily against HA (Wright and Webster, 2001).However, the antigenic structure of the HA of influenza A virus canundergo two types of change (Wright and Webster, 2001). Antigenic driftresults from the selection of mutant viruses that evade antibodiesdirected against the major antigenic type of the HA circulating in thehuman population. Mutant viruses are readily generated because the viralRNA polymerase has no proof-reading function. Because of antigenicdrift, the vaccine has to be reformulated each year. Antigenic shift inHA results from reassortment of genomic RNA segments between human andavian influenza A virus strains, resulting in a new (potentiallypandemic) virus encoding a novel avian-type HA that is immunologicallydistinct. The human population has little or no immunological protectionagainst such a new virus. The viruses containing the H2 and H3 HAsubtypes that caused pandemics in 1957 and 1968, respectively, resultedfrom the reassortment of avian and human genomic RNA segments (Wrightand Webster, 2001). The HA of influenza B viruses undergoes antigenicdrift, but not antigenic shift, because influenza B viruses do not havenon-human hosts.

Pandemic influenza A viruses can also apparently arise by a differentmechanism. It has been postulated that the 1918 H1 pandemic strainderived all eight genomic RNAs from an avian virus, and that this virusthen underwent multiple mutations in the process of adapting tomammalian cells (Reid et al., 2004; Taubenberger et al., 2005). H5N1viruses, which have already spread from Asia to Europe and Africa,appear to be undergoing this route for acquiring pandemic capability(Horimoto and Kawaoka, 2005; Noah and Krug, 2005). These viruses, whichhave been directly transmitted from chickens to humans, contain onlyavian genes, and are highly pathogenic in humans. The human mortalityrate has been high, approximately 55% (WHO, 2006). H5N1 viruses have notyet acquired the ability for efficient transmission from humans tohumans. Recent studies indicate that efficient human transmission willrequire more than the acquisition of the ability of HA to bind to humansialic acid receptors in the upper respiratory tract of mammalianorganisms (Maines et al., 2006). However, at least one H5N1 gene, thePB2 gene, has already undergone adaptation to mammalian cells (Hatta etal., 2001). The vast majority of pathogenic H5N1 viruses have acquired alysine at position 627 in the PB2 protein, in place of the glutamic acidthat is found at this position in avian viruses. The presence of lysineat this position apparently enhances virus replication in mammaliancells, but the mechanism of enhancement has not been established(Crescenzo-Chaigne et al., 2002; Shinya et al., 2004).

Effective control of a H5N1 pandemic will require the use of antiviraldrugs because it is not likely that sufficient amounts of an effectivevaccine will be available, particularly in the early phase of afast-spreading pandemic (Ferguson et al., 2005; Longini et al., 2005;Ferguson et al., 2006; Germann et al., 2006). Antivirals can bestockpiled, and if appropriately used, should limit the spread ofpandemic influenza virus. The strategies that have been proposed for theuse of antivirals to stem a H5N1 pandemic would also be expected to leadto more effective use of antivirals during annual influenza epidemics.Currently, there are two classes of antiviral drugs. One class,amantadine/rimantidine, is directed against the M2 ion channel ofinfluenza A viruses (Pinto et al., 1992; Wang et al., 1993; Chizhmakovet al., 1996). Virus mutants resistant to this class of drugs rapidlyemerge (Cox and Subbarao, 1999; Suzuki et al., 2003), and many of thehuman isolates of H5N1 viruses are already resistant to these drugs(Puthavathana et al., 2005). The other class of drugs is directed at NA,and is effective against both influenza A and B viruses (von Itzstein etal., 1993; Woods et al., 1993; Ryan et al., 1994; Gubareva et al., 1995;Kim et al., 1997; Mendel et al., 1998). However, H5N1 viruses that arepartially, or completely, resistant to the NA inhibitor oseltamivir havebeen reported (de Jong et al., 2005; Le et al., 2005). The emergence ofH5N1 viruses to these two classes of antiviral drugs highlights the needfor additional antiviral drugs against influenza virus.

SUMMARY OF THE INVENTION

The present invention includes the structure and function of thecellular polyadenylation and specificity factor 30 (CPSF30) bindingsite, or “binding epitope”, on the surface of the influenza Anon-structural protein 1 (NS1). When referring to influenza A, theprotein is referred to herein as NS1A. The NS1 protein of influenza Avirus will be designated as the NS1A protein to distinguish it from theNS1 protein encoded by influenza B virus, which will be designated asthe NS1B protein. Several fragments of the NS1A protein were identified,from various influenza strains, that provide high-level expression andsolubility in E. coli expression systems. The present invention alsoincludes expression systems and protocols for producing large quantitiesof the previously identified F2F3 fragment of human CPSF30, which bindsto the NS1A effector domain (Twu et al., 2006). These fragments of theNS1A protein and of CPSF30 provide high quality NMR spectra, suitablefor lead compound optimization. Combining these reagents andinformation, we have designed a gel filtration assay suitable forcharacterizing complex formation between NS1A and CPSF30 (or fragmentsthereof), as well as a fluorescence polarization (FP) assay ofNS1A-CPSF30 interactions that is suitable for high throughput screeningfor lead compounds to develop antiviral drugs. Using these reagents,complexes of the tetrameric complex between the NS1A effector domain andF2F3 were also generated. We have also developed a process forcrystallizing this complex. These crystals were used to determine the 3Dstructure of the NS1A effector domain: F2F3 complex, and to definitivelyidentify for the first time all the NS1A amino acids that comprise aportion of the CPSF30 binding epitope in the NS1A protein. Thesereagents and structural data, together with specific site-directedmutagenesis data, have allowed us to define a structure-based processfor high-throughput screening of inhibitors and lead optimization thatwill allow development of influenza A antiviral drugs. Also disclosed isa process using these reagents and structural data to develop attenuatedstrains of influenza A suitable for use as animal (e.g. avian) or humanvaccines.

Using the present invention it is possible for antiviral drug(s) to bedirected at a viral target that differs from that of currently availableinfluenza antivirals. Novel approaches are important because influenza Aviruses, including avian influenza virus, are developing resistance toexisting antiviral drugs. The present invention also describes a processfor developing vaccines using structural information that has not beenpreviously disclosed. A vaccine using live attenuated strains ofinfluenza A virus is expected to provide better protection than avaccine using inactivated virus. The present invention may also be usedto develop, isolate and characterize antiviral drugs and live attenuatedvirus vaccine for both seasonal and pandemic influenza virus infections.

More particularly, the present invention includes a complex of the F2F3fragment of CPSF30 with the portion of the NS1A protein of influenza Avirus comprising amino acid residues 85 to 215 (NS1A (85-215)). Thecomplex can be used in a method of identifying an inhibitor of influenzaA virus by preparing a reaction system comprising at least a portion ofNS1A of an influenza A virus, the F2F3 fragment of CPSF30, and acandidate compound; and detecting binding between the at least a portionof NS1A and F2F3, wherein reduced binding in the presence of thecandidate drug relative to the control is indicative of activity of thecompound against influenza virus. Examples of the NS1A fragments arelisted in Table 2, and may also include the full length NS1A, andmutations thereof. The skilled artisan will recognize that the NS1Aprotein fragment may be prepared from other strains of influenza Aviruses, e.g., human influenza A virus, a bovine influenza A virus, anequine influenza A virus, a porcine influenza A virus, an avianinfluenza A virus, an avian H5N1 viral strain.

For use with the present invention, the CPSF30 may be, e.g., a fulllength CPSF30, F3 zinc-finger domain, an F2F3-F2F3 tandem duplex, anF1F2F3 fragment, a soluble fragment of CPSF30, combinations and mutantsthereof. Detection of the binding may be by, e.g., a high throughputscreening assay, X-ray crystallography, nuclear magnetic resonance,analytical gel filtration, and combinations thereof. Other methods ofdetecting the interaction of the NS1A and CPSF30 (or portions thereof)may be, e.g., fluorescence resonance energy transfer, fluorescencepolarization, immunofluorescence, chemiluminescence, radioimmunoassays,enzyme linked immunosorbent assays, mass spectrometry, and combinationsthereof. For example, fluorescence polarization may use either afluorescent labeled CPSF30, variant or fragment thereof or a fluorescentlabeled NS 1A protein, variant or fragments thereof.

The present invention also includes a process for using 3D(three-dimensional) information of the CPSF30 binding epitope on theinfluenza A virus NS1A protein for identifying inhibitors of aninfluenza A virus by obtaining concurrently the coordinates for themolecular position of at least a portion of an influenza NS1A proteinand at least a portion of a CPSF30 protein and designing a molecule thatwill fit between the influenza NS1A protein and the CPSF30 protein basedon the coordinates. The portion of the NS1A protein and the portion ofthe CPSF30 protein will generally be selected to provide high qualityNMR spectra, e.g., the NS1A (85-215) fragment and the F2F3 fragment maybe selected to form a tetrameric complex.

In another example, the NS1A (85-215) fragment and the F2F3 fragment mayform a tetrameric complex that is crystallized. Other examples may usean NS1A (85-215) fragment and the F2F3 fragment form a tetramericcomplex that is crystallized and is used to determine the 3D structureof the NS1A (85-215):F2F3 complex using X-ray crystallography. Themethod may also include the step of identifying the NS1A amino acidsthat constitute the CPSF30 binding portion of the NS1A protein.

Yet another embodiment is a method of designing an inhibitor compound ofan influenza A virus based on computational methods, wherein theinhibitor that binds at least one residue within the set of residuescorresponds to the structure, using the crystal structure and itscoordinates. The design method may be facilitated by using NMR spectraof samples of NS1A protein fragments, NMR spectra of samples ofNS1A(85-215) or equivalent constructs thereof. The method may furtherinclude the step of optimizing the design of the molecule that fitsbetween the NS1A (85-215) protein and the CPSF30 protein using X-raycrystallography, and synthetic chemistry. The method of designing aninhibitor compound may also include the step of optimizing the design ofthe molecule that fits between the NS1A(85-215) protein and the CPSF30protein using X-ray crystallography, NMR, synthetic chemistry andcombinations thereof. Another embodiment of method of designing aninhibitor compound may also include, optionally or in combination one ormore of the following: modifying the F2F3 structure of CPSF30, or anysubstructure, based on its conformation bound to NS1A to rationallydesign one or more small molecule inhibitors; modifying the F2F3structure of CPSF30, or any substructure, to rationally design one ormore small molecule inhibitors based on its conformation bound to NS1Aof the F2F3 aromatic rings, the sidechain of residue Lys101, orcombinations thereof; modifying the F2F3 structure of CPSF30, or anysubstructure, to rationally design one or more small molecule inhibitorsby virtual screening; using the three-dimensional structure of the NS1Abinding pocket to select one or more small molecule inhibitors or usingthe three-dimensional structure of the NS1A binding pocket to select oneor more small molecule inhibitors by virtual screening. Any fragmentsof, full length, and strains of NS1A, and fragments of, full length, andstrains of CPSF30 and combinations thereof may be used in conjunctionwith the method of designing an inhibitor compound.

Another embodiment of the present invention includes a process forengineering a live attenuated influenza A virus vaccine by mutation ofspecific residues in the CPSF30-binding epitope of the NS1A proteinbased on the 3D structure of the complex formed between NS1A (85-215)and F2F3, a tetramer interface and combinations thereof. Specificexamples of residues at the tetramer interface site include, e.g., F103,L105, M106 and equivalents thereof. Specific examples of residues at theCPSF30-binding epitope include, e.g., M106, K110, I117, I119, Q121,D125, V180, G183, G184, W187 and equivalents thereof. The process mayfurther include mutating the double-strand RNA binding epitope.

Another embodiment of the present invention includes an attenuatedinfluenza A virus vaccine that includes one or more of eight viral RNAsegments, wherein a viral RNA segment eight has a first mutation thatcauses a substitution of a first amino acid corresponding to an aminoacid of SEQ. ID. NO. 1 at a position F103, L105, M106, K110, I117, I119,Q121, D125, L144, V180, G183, G184, or W187; wherein the first mutationdecreases the CPSF30 binding ability of the NS1A protein. In oneembodiment, at least a second mutation anywhere in the NS1A protein. Thevaccine may also include at least second mutation causes a substitutionof at least a second amino acid corresponding to an amino acid of SEQ IDNO.: 1 at a position F103, L105, M106, K110, I117, I119, Q121, D125,L144, V180, G183, G184, W187 and equivalents thereof. Alternatively, thevaccine may also include at least second mutation with a substitution ofat least a second amino acid corresponding to an amino acid of SEQ IDNO.: 1 at a position T5, P31, D34, R35, R38, K41, G45, R46, and T49 at adsRNA binding epitope and equivalents thereof. Alternatively, thevaccine may also include at least second mutation with at least secondmutation causes a substitution of at least a second and third amino acidcorresponding to an amino acid of SEQ. ID. NO. 1 at a position T5, P31,D34, R35, R38, K41, G45, R46, and T49 at a dsRNA binding epitope and/orF103, L105, M106, K110, I117, I119, Q121, D125, L144, V180, G183, G184,W187 and equivalents thereof. The influenza virus is a may be acold-adapted influenza virus and will generally be selected to elicit animmune response. Non-limiting examples of influenza virus that may beused to make the attenuated vaccine may be is selected from, e.g., ahuman influenza A virus, a bovine influenza A virus, an equine influenzaA virus, a porcine influenza A virus, an avian influenza A virus, anavian H5N1 viral strain.

The present invention also includes a pharmaceutical composition havinga live attenuated influenza A virus vaccine by mutation of specificresidues in the CPSF30-binding epitope of the NS1A protein based on the3D structure of the complex formed between NS1A (85-215) and F2F3, atetramer interaction site and combinations thereof and apharmaceutically acceptable carrier or diluent. The vaccine may be usedin a method of prophylaxis of a disease condition caused by theinfluenza virus by administering to a subject in need thereof atherapeutically effective amount of a live attenuated influenza A virusvaccine by mutation of specific residues in the CPSF30-binding epitopeof the NS1A protein based on the 3D structure of the complex formedbetween NS1A (85-215) and F2F3, a tetramer interaction site, the dsRNAbinding epitope and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIGS. 1A and 1B are graphs that show the effects on the growth of arecombinant influenza A virus resulting from mutations in its ofmutations on NS1A protein that relate to the ability of the NS1A to bindto CPSF30;

FIG. 2 shows NMR spectra of certain NS1A effector domains, demonstratingthat such data can be used for structure-function analysis, inhibitordiscovery and optimization, and in validating the effects of mutationson the structure of the effector domain;

FIG. 3 shows the results from analytical gel filtrations assays of NS1A(85-215):F3F3 binding;

FIG. 4A shows the X-ray crystal structure of a tetrameric NS1A effectordomain and F2F3;

FIG. 4B shows the X-ray crystal structure for the Met106 residue in thecore of the tetrameric NS1A (85-215):F2F3 complex;

FIG. 5 shows the X-ray crystal structure for the F2F3 binding epitope onthe surface of the NS1A effector domain;

FIG. 6 is a comparison of 3D structures for Udorn and PR8 NS1A effectordomains; and

FIG. 7 shows the 3D structure and dimeric beta-sheet interface of thePR8 effector domain, which does not bind F2F3.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The specificembodiments discussed herein are merely illustrative of specific ways tomake and use the invention and do not delimit the scope of theinvention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

One of the best clues to a protein's function is its structure. Thepresent invention takes advantage of structure-based bioinformaticsplatforms in “functional genomics.” The structure-function data obtainedfrom various structural determination may be used the isolation of novelbiopharmaceuticals and/or drug targets from gene sequence informationwith greater efficiency. One way to identify the biochemical and medicalfunction of a gene product is to determine its three-dimensionalstructure. Although there are numerous examples in which the primary(i.e., linear) structure of a protein has provided key clues to itsbiochemical function, three dimensional (3D) structure determination isconsidered to be more definitive at establishing biochemical functionand mechanisms underlying these functions.

Protein structure. It is a generally accepted principle of biology thata protein's primary sequence is the main determinant of its tertiarystructure. Anfinsen, Science 181:223-230 (1973); Anfinsen and Scheraga,Adv. Prot. Chem. 29:205-300 (1975); and Baldwin, Ann. Rev. Biochem.44:453-475 (1975). For over a decade, researchers have been studying thetheoretical and practical aspects of the folding of recombinantproteins.

Generally, proteins are composed of one or more autonomously-foldingunits known as domains. Kim, et al., Ann. Rev Biochem. 59:631-660(1990); Nilsson, et al., Ann. Rev. Microbiol. 45:607-635 (1991).Multi-domain proteins in higher organisms are encoded by genescontaining multiple exons and combinatorial shuffling of exons duringevolution has produced novel proteins with different domain arrangementshaving different associated functions. Multi-domain protein may increasethe ability of higher organisms to respond to environmental challengesbecause, via recombinational events, because the genomes may readilyadd, subtract, or rearrange discrete functionalities within a givenprotein. Patthy, Cell 41:657-663 (1985); Patthy, Curr. Opin. Struct.Bio. 4:383-392 (1994); and Long, et al., Science 92:12495-12499 (1995).

Interpretation of a protein structure. Several methods have been used toelucidate the 3D structure of a given protein molecule, e.g., X-raycrystallography and Nuclear Magnetic Resonance (NMR).

X-ray crystallography. X-ray crystallography is a technique thatdirectly images molecules. A crystal of the molecule to be visualized isexposed to a collimated beam of monochromatic X-rays and the consequentdiffraction pattern is recorded on a photographic film or by a radiationcounter. The intensities of the diffraction maxima are then used toconstruct mathematically the three-dimensional image of the crystalstructure. X-rays interact almost exclusively with the electrons in thematter and not the nuclei. The spacing of atoms in a crystal lattice canbe determined by measuring the angle and intensities at which a beam ofX-rays of a given wave length is diffracted by the electron shellssurrounding the atoms. Operationally, there are several steps in X-raystructural analysis. The amount of information obtained depends on thedegree of structural order in the sample. Blundell et al. provide anadvanced treatment of the principles of protein X-ray crystallography.Blundell, et al., Protein Crystallography, Academic Press (1976), hereinincorporated by reference. Likewise, Wyckoff et al. provide a series ofarticles on the theory and practice of X-ray crystallography. Wyckoff,et al. (Eds.), Methods Enzymol. 114: 330-386 (1985), relevant portionsherein incorporated by reference. Important techniques for X-raycrystallography include methods for determining diffraction data phasesby a multiple anomalous dispersion (MAD) method (described, for example,in Hendrickson, 1991), particularly using biosynthethic enrichment withseleno-methione (SeMet), and a molecular replacement method (described,for example, in Rossmann, M. G. The molecular replacement method. ActaCryst. A46, 73-82 (1990).

Nuclear Magnetic Resonance (NMR). A general approach for the analysis ofNMR resonance assignments was first outlined by Wuthrich, Wagner andco-workers. Wuthrich, “NMR of proteins and nucleic acids” Wiley, NewYork, N.Y. (1986); Wuthrich, Science 243:45-50 (1989); Billeter, et al.,J. Mol Biol. 155:321-346 (1982), relevant portions of each incorporatedherein by reference. For a general review of protein determination insolution by nuclear magnetic resonance spectroscopy, see Wuthrich,Science 243:45-50 (1989); Billeter et al., J. Mol. Biol. 155:321-346(1982). More recent improvements using multidimensional and tripleresonance NMR methods (described, for example, in J. Cavanagh, W.Fairbrother, A. Palmer, and N. Skelton, Protein NMR Specroscopy,Principles and Practice, 2ed Ed, Academic Press, NY, 2006, incorporatedherein), familiar to someone trained in the art, are elaborations ofthese basic principles.

As used herein, the terms “CPSF30 binding epitope” or “CPSF bindingsite” refer to that portion of the NS1 protein of influenza thatinteracts with one or more zinc fingers of the CPSF30 protein.

As used herein, the terms “NS1A-binding epitope” or “NS1A binding site”refer to that portion of the CPSF30 protein that interacts with the NS1protein of influenza A.

As used herein, the term “tetramer interface” refers to those portionsof the NS1A protein and the CSPF30 protein that interact NS1A:CPSF30complex, which can be a dimer or tetramer.

As used herein, the terms “double-strand RNA binding site” or“doubled-stranded RNA binding epitope” refer to that portion of the NS1Aprotein that interacts with double-stranded RNA, e.g., for suppressinghost innate immune response. Greater structural details regarding thedouble-strand RNA binding site is taught by the present co-inventors inPCT/US2003/036,292, “Process for Designing Inhibitors of Influenza VirusNon-Structural Protein 1,” relevant portions incorporated herein byreference and U.S. Provisional Patent Application Ser. No. 60/737,742,“Novel Compositions and Vaccines Against Influenza and Influenza BInfections,” and PTC Patent Application Filed Nov. 17, 2006 “NovelCompositions and Vaccines Against Influenza and Influenza B Infections,”relevant portions and tables incorporated herein by reference.

As used herein, the term “epitope” refers to a portion of a protein thatis capable of interacting with the same or another protein and that canbe define by atoms in amino acids in a linear sequence, by atoms inamino acids that are located throughout the protein (or subunitsthereof) and that come together in three dimensions to form aninteractive structure. The skilled artisan will recognize that anepitope may be a structure such as a “zinc finger,” a portion of amolecular surface between two or more polypeptides that are capable ofinteracting, and/or a “binding pocket” or “enzymatic pocket” that leadto a function or interaction of the protein.

As used herein, the following nomenclature is used to define the zincfinger domains of the CPSF30 protein that interact NS1A, namely, “F1”,“F2” and “F3” when referring to individual zinc fingers, “F1F2”, “F2F3”when referring to a pair of zinc fingers and “F1F2F3” when referring tothe three zinc fingers.

As used herein, the term “rationally design” refers to a series of stepsfor designing, e.g., initial small molecule inhibitors that may befurther refined through medicinal chemistry and/or the selection ofinhibitors that can be further modified chemically and that fit themolecular characteristics of a molecule that will meet the designcriteria for modifying the interactions between or the activity of NS1Aand CPSF30 based fully and/or at least in part on the three dimensional(3D) coordinates described herein.

As used herein, the term “virtual screening” refers to in silico design,using computer software to screen for possible binding ligands from alibrary of virtual molecules, allowing the characterization andrefinement of small molecule inhibitors that will meet the designcriteria for modifying the interactions between or the activity of NS1Aand CPSF30 based fully and/or at least in part on the three dimensional(3D) coordinates described herein.

As used herein, the term “corresponding positions” refers to amino acidsat that are generally in the same spatial location in thethree-dimensional structures of homologous protein structures. In oneexample, a corresponding position is determined by 3D structurealignment using standard techniques known to a person skilled in theart, such as the PRISM program, described by Yang and Hong Yang, A.-S.and Honig, B. (2000) An Integrated Approach to the Analysis of Sequenceand Structure. I. Protein Structural Alignment and a QuantitativeMeasure for Protein Structural Distance. J. Mol. Biol. 301: 665-678;Yang, A.-S. and Honig, B. (2000) An Integrated Approach to the Analysisof Sequence and Structure. III. A Comparative Study of SequenceConservation in Protein Structural Families Using Multiple StructuralAlignments, or the VISTAL program, described by Kolodny, R. and Honig,B. (2006) VISTAL—A New 2D Visualization Tool of Protein 3D StructuralAlignments. Bioinformatics 22:2166-2167 (e.g., using the defaultsettings for either), relevant portions incorporated herein byreference. The alignment may include the introduction of gaps in thesequences to be aligned. In the absence of 3D structures for proteinpairs, corresponding positions may be identified (until such time thatthe requisite 3D structures are available) by sequence-based alignmentusing standard techniques known to a person skilled in the art, such asa Needleman-Wunsch dynamic programming algorithm (described inNeedleman, S. B. and Wunsch, C. D., J Mol Biol. 48: 443-453 (1970), aGapped BLAST/PSI-BLAST algorithm (described in Altschul, et al Nucl.Acid. Res. 25: 3389-3402 (1997), or a CLUSTAL W/X multiple sequencealignment algorithm (described in Thompson, J. D., Higgins, D. G. andGibson, T. J. (1994) CLUSTAL W: improving the sensitivity of progressivemultiple sequence alignment through sequence weighting, positionspecific gap penalties and weight matrix choice. Nucl. Acid. Res.22:4673-80 (1994).) (e.g., using the default settings for eitherrelevant portions incorporated herein by reference. Correspondingposition alignment(s) may also include the introduction of gaps in thesequences to be aligned.

Further examples of “corresponding positions are taught by the presentco-inventors in PCT/US2003/036,292, “Process for Designing Inhibitors ofInfluenza Virus Non-Structural Protein 1,” relevant portionsincorporated herein by reference and U.S. Provisional Patent ApplicationSer. No. 60/737,742, “Novel Compositions and Vaccines Against Influenzaand Influenza B Infections”, and PTC Patent Application Filed Nov. 17,2006 “Novel Compositions and Vaccines Against Influenza and Influenza BInfections,” relevant portions and tables incorporated herein byreference.

Non-limiting examples of numerous influenza A strains may be used withthe present invention including those strains that are readily availableor will become available as they emerge in human populations. Examplesof influenza A strains for use and analysis with the present inventionmay include A/Memphis/8/88, A/Chile/1/83, A/Kiev/59/79, A/Udorn/307/72,A/NT/60/68, A/Korea/426/68, A/Great Lakes/0389/65, A/Ann Arbor/6/60,A/Leningrad/13/57, A/Singapore/1/57, A/PR/8/34, A/Vietnam/1203/04,A/HK/483/97, A/South Carolina/1/181918 (the 1918 pandemic virus H1N1strain), and A/WSN/33. The sequences of these strains are available fromGenBank, CDC and viral stock may be available from the American TypeCulture Collection, Rockville, Md. or are otherwise publicly available.

As used herein, the term “variant” gene or protein refers to a gene orprotein that differs from the wild type gene or protein by way ofnucleotide or amino acid substitution(s), addition(s), deletion(s), andcombinations thereof. Depending on the context, the term mutant is alsoused to describe variations from the wild-type sequence that arenatural, introduced at random and/or introduced into a gene or proteinsequence specifically. Likewise, a fragment is used to describe afragment of the complete length of the translated polypeptide, whethernatural or not. Often, the skilled artisan will design fragments thatinclude or avoid certain amino acid that may affect, e.g., synthesis orcause steric hindrance or other design requirements. When designingalternate peptide constructs with enhanced anti-viral properties,substitutions may be used which modulate one or more properties of themolecule. Variants typically include the exchange of one amino acid foranother at one or more sites within the peptide. For example, certainamino acids may be substituted for other amino acids in a peptidestructure in order to enhance the interactive binding capacity of thestructures. Certain amino acid substitutions can be made in a proteinsequence (or its underlying DNA coding sequence) to create a peptidewith superior functional characteristics. In particular, those changesthat enhance the amphipathic, α-helical nature may be desired.

As used herein, the term “candidate compound” refers to any moleculethat may inhibit influenza viral growth. The candidate substance may bea protein or fragment thereof, a small molecule, or even a nucleic acidmolecule. Various commercial sources of small molecule libraries meetthe basic criteria for useful drugs in an effort to “brute force” theidentification of useful candidate compounds. Screening of suchlibraries, including libraries generated combinatorially (e.g., peptidelibraries, aptamer libraries, small molecule libraries), is a rapid andefficient way to screen large number of related (and unrelated)compounds for activity. Combinatorial approaches also lend themselves torapid evolution of potential drugs by the creation of second, third andfourth generation compounds modeled of active, but otherwise undesirablecompounds. Candidate compounds may be screened from large libraries ofsynthetic or natural compounds. One example of a candidate compoundlibrary is an FDA-approved library of compounds that can be used byhumans. Synthetic compound libraries are commercially available from anumber of companies including Maybridge Chemical Co. (Trevillet,Cornwall, UK), Comgenex (Princeton, N.J.), Brandon Associates(Merrimack, N.H.), and Microsource (New Milford, Conn.) and a rarechemical library is available from Aldrich (Milwaukee, Wis.).Combinatorial libraries are available or can be prepared. Alternatively,libraries of natural candidate compounds in the form of bacterial,fungal, plant and animal extracts are also available from, for example,Pan Laboratories (Bothell, Wash.) or MycoSearch (N.C.), or can bereadily prepared by methods well known in the art. Candidate compoundsisolated from natural sources, such as animals, bacteria, fungi, plantsources, including leaves and bark, and marine samples may be assayed ascandidates for the presence of potentially useful pharmaceutical agents.It will be understood that the pharmaceutical agents to be screenedcould also be derived or synthesized from chemical compositions orman-made compounds.

The amino acid sequence of the NS1A protein of Influenza A virus,A/Udorn/72:

(SEQ ID NO.: 1)   1MDPNTVSSFQ VDCFLWHVRK RVADQELGDA PFLDRLRRDQ KSLRGRGSTL GLDIETATRA  61GKQIVERILK EESDEALKMT MASVPASRYL TDMTLEEMSR EWSMLIPKQK VAGPLCIRMD 121QAIMDKNIIL KANFSVIFDR LETLILLRAF TEEGAIVGEI SPLPSLPGHT AEDVKNAVGV 181LIGGLEWNDN TVRVSETLQR FAWRSSNENG RPPLTPKQKR EMAGTIRSEV.

The anti-viral agents disclosed herein may be used in conjunction withmethods to reduce virus growth, infectivity, burden, shed, developmentof anti-viral resistance, and to enhance the efficacy of traditionalanti-viral therapies.

The amino acid sequence of the relevant fragments of human CPSF30(UniProt id 095639):

(SEQ ID NO.: 13)   1MQEIIASVDH IKFDLEIAVE QQLGAQPLPF PGMDKSGAAV CEFFLKAACG  50  51KGGMCPFRHI SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKMPECYFYS 100 101KFGECSNKEC PFLHIDPESK IKDCPWYDRG FCKHGPLCRH RHTRRVICVN 150 151YLVGFCPEGP SCKFMHPRFE LPMGTTEQPP LPQQTQPPAK QSNNPPLQRS 200 201SSLIQLTSQN SSPNQQRTPQ VIGVMQSQNS SAGNRGPRPL EQVTCYKCGE 250 251KGHYANRCTK GHLAFLSGQ

The amino acid sequence of the relevant fragments of human CPSF30discussed in this patent are:

F1 Zn-Finger Domain: residues 41-59;

F2 Zn-Finger Domain: residues 68-86;

F3 Zn-Finger Domain: residues 96-114;

F4 Zn-Finger Domain: residues 124-142;

F5 Zn-Finger Domain: residues 148-166; and

F5 Zn-Finger Domain: residues 243-260.

As used herein F2F2 are residues 61-121 of SEQ ID NO.: 13:

 61 SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKMPECYFYS 100 101KFGECSNKEC PFLHIDPESK I 121

As used herein F1F2F3 are residues 39-121 of SEQ ID NO.: 13:

 39 AV CEFFLKAACG  50  51KGGMCPFRHI SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKMPECYFYS 100 101KFGECSNKEC PFLHIDPESK 121

The anti-viral properties of the peptides disclosed herein allow them tobe included in formulations to inhibit virus growth and proliferation.The purified anti-viral peptides may be used without furthermodifications or they may be diluted in a pharmaceutically acceptablecarrier. The invention may be administered to humans or animals,included in food and pharmaceutical preparations. They anti-viral agentsmay also be used in medicinal and pharmaceutical products (such as fluidcontainers, iv. bags, tubing, syringes, etc.), as well as in cosmeticproducts, hygienic products, cleaning products and cleaning agents, aswell as any material to which the peptides could be sprayed on oradhered to wherein the inhibition of virucidal growth on such a materialis desired.

The dosage of an anti-viral peptide necessary to prevent viral growthand proliferation depends upon a number of factors including the typesof virus that might be present, the environment into which the peptideis being introduced, and the time that the peptide is envisioned toremain in a given area.

As used herein, the phrases “pharmaceutically” or “pharmacologicallyacceptable” refer to molecular entities and compositions that do notproduce adverse, allergic, or other untoward reactions when administeredto an animal or a human. As used herein, “pharmaceutically acceptablecarrier” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The use of such media and agents forpharmaceutically active substances is well know in the art. Exceptinsofar as any conventional media or agent is incompatible with thevectors or cells of the present invention, its use in therapeuticcompositions is contemplated. Supplementary active ingredients also canbe incorporated into the compositions.

The active antiviral agents of the present invention may be formulatedinto classic pharmaceutical preparations and administered via any commonroute so long as the target tissue is available via that route. Theseroutes of administration include, e.g., oral, alveolar, nasal, buccal,rectal, vaginal or topical. In particular, use of the anti-viralpeptides of the present invention in a condom or diaphragm, optionallyin conjunction with a spermicidal or other contraceptive substance, isenvisioned. Alternatively, administration may be orthotopic,intradermal, subcutaneous, intramuscular, intraperitoneal orintravenous. The antiviral agent may also be administered parenterallyor intraperitoneally. Solutions of the antiviral agent may be compoundedinto a free base or pharmacologically acceptable salts can be preparedin water suitably mixed with a surfactant, such ashydroxypropylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms.

The antiviral agent(s) will generally be provided in a pharmaceuticaldosage form suitable for injectable use, e.g., sterile aqueous solutionsor dispersions and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersions. For widespread use, theantiviral agents may be stable under the conditions of manufacture andstorage and must be preserved against the contaminating action ofmicroorganisms, such as bacteria and fungi. The antiviral agents willcommonly be provided with a carrier, e.g., a solvent or dispersionmedium that may include, e.g., water, ethanol, polyol (for example,glycerol, propylene glycol, and liquid polyethylene glycol, and thelike), suitable mixtures thereof, and vegetable oils. Proper dosagefluidity can be maintained, for example, by the use of a coating, suchas lecithin, by the maintenance of the required particle size in thecase of dispersion and by the use of surfactants. The prevention of theaction of microorganisms can be brought about by various antibacterialand/or antifungal agents, for example, parabens, chlorobutanol, phenol,sorbic acid, thimerosal, and the like. In many cases, the dosage formwill include isotonic agents, e.g., sugars or sodium chloride. Prolongedabsorption of the injectable compositions can be brought about by theuse in the compositions of agents delaying absorption, for example,aluminum monostearate and gelatin.

Generally, sterile injectable solutions are prepared by incorporatingthe active compounds in the required amount in the appropriate solventwith various of the other ingredients enumerated above, as required,followed by sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle that includes the basic dispersion medium and the required otheringredients from those enumerated above. Preparation of sterile powdersfor injectable solutions maybe prepared by, e.g., vacuum-drying,spray-freezing, freeze-drying or other techniques that yield a powder ofthe active ingredient plus any additional desired ingredient from apreviously sterile-filtered solution thereof.

As used herein, a “pharmaceutically acceptable carrier” refers tosolvents, dispersion media, coatings, antibacterial and anti-fungalagents, isotonic and absorption delaying agents and the like. The use ofsuch media and agents for pharmaceutical active substances is well knownin the art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

For oral administration, the antiviral agent(s) of the present inventionmay be incorporated with excipients and used in the form of ingestibleor non-ingestible mouthwashes and dentifrices. A mouthwash may beprepared incorporating the active ingredient in the required amount inan appropriate solvent, such as a sodium borate solution (Dobell'sSolution). Alternatively, the antiviral agent(s) may be incorporatedinto an antiseptic wash containing sodium borate, glycerin and potassiumbicarbonate. The antiviral agent(s) may also be dispersed indentifrices, e.g., gels, pastes, powders and slurries. The antiviralagent(s) may be added in a therapeutically effective amount to a pastedentifrice that may include water, binders, abrasives, flavoring agents,foaming agents, and humectants.

The antiviral agent(s) may be formulated in a neutral or salt form.Pharmaceutically-acceptable salts include the acid addition salts(formed with the free amino groups of the protein) and which are formedwith inorganic acids such as, for example, hydrochloric or phosphoricacids, or such organic acids as acetic, oxalic, tartaric and the like.Salts may also be formed with the free carboxyl groups can also bederived from inorganic bases such as, for example, sodium, potassium,ammonium, calcium, or ferric hydroxides, and such organic bases asisopropylamine, trimethylamine, histidine, procaine and the like.

Upon formulation, the antiviral agent(s) will be administered in amanner compatible with the dosage formulation and in such amount as istherapeutically effective. The formulations are easily administered in avariety of dosage forms such as injectable solutions, drug releasecapsules and the like. Sterile aqueous media that can be employed willbe known to those of skill in the art in light of the presentdisclosure, e.g., Remington: The Science and Practice of Pharmacy, 21stEdition, Lippincott Williams & Wilkins (2005), relevant portionsincorporated herein by reference. Some variation in dosage willnecessarily occur depending on the condition of the subject beingtreated for which the skilled artisan will determine the appropriatedose for the individual subject. Moreover, for human administration,preparations should meet sterility, pyrogenicity, general safety andpurity standards as required by FDA Office of Biologics standards.

In one embodiment, the vaccine comprises a pharmaceutically acceptablevehicle. The suitable vehicles may be both aqueous and non-aqueous.Examples of non-aqueous solvents are propylene glycol, polyethyleneglycol, vegetable oils such as olive oil, and injectable organic esterssuch as ethyl oleate. Carriers or occlusive dressings can be used toincrease skin permeability and enhance antigen absorption. Liquid dosageforms for oral administration may generally comprise a liposome solutioncontaining the liquid dosage form. Suitable forms for suspendingliposomes include emulsions, suspensions, solutions, syrups, and elixirscontaining inert diluents commonly used in the art, such as purifiedwater.

Besides the inert diluents, such compositions can also includeadjuvants, immunostimulats, immunosuppressants, wetting agents,emulsifying and suspending agents, or any combination thereof.

Examples of suitable adjuvants include, without limitation, incompleteFreund's adjuvant, aluminum phosphate, aluminum hydroxide, or alum,Stimulon® QS-21 (Aquila Biopharmaceuticals, Inc., Framingham, Mass.),MPL® (3-0-deacylated monophosphoryl lipid A; Corixa, Hamilton, Mont.),and interleukin-12 (Genetics Institute, Cambridge, Mass.).

A person of the ordinary skill in the art has a sufficient expertise todetermine the dosage of the vaccines of the instant invention. Suchdosage depends on the pathogenicity of the virus included in the vaccineand on the ability of the antigen to elicit an appropriate immuneresponse. In different embodiments of the invention, a virus vaccinecomposition of the instant invention may comprise from about 10²-10⁹plaque forming units (PFU)/ml, or any range or value therein (e.g., 10³,10⁴, 10⁵, 10⁶, 10⁷, or 10⁸) where the virus is attenuated. A vaccinecomposition comprising an inactivated virus can comprise an amount ofvirus corresponding to about 0.1 to 200 μg of the amino acid sequencesof the instant invention per ml, or any range or value therein.

The vaccines of the instant invention can be applied in multiple ways.According to one embodiment of the invention, the intranasaladministration is via the mucosal route. The intranasal administrationof the vaccine composition can be formulated, for example, in liquidform such as, for example, nose drops, spray, or suitable forinhalation. In other embodiment, the vaccine may be administered as apowder, or a cream, or an emulsion.

In another embodiment, the vaccines of the instant invention are appliedby an injection, including, without limitation, intradermal,transdermal, intramuscular, intraperitoneal and intravenous. Accordingto another embodiment of the invention, the administration is oral andthe vaccine may be presented, for example, in the form of a tablet orencased in a gelatin capsule or a microcapsule, which simplifies oralapplication. The production of these forms of administration is withinthe general knowledge of a technical expert.

As used herein, “detectable labels” refer to compounds and/or elementsthat can be detected due to their specific functional properties and/orchemical characteristics, the use of which allows the agent to whichthey are attached to be detected, and/or further quantified if desired,such as, e.g., an enzyme, an antibody, a linker, a radioisotope, anelectron dense particle, a magnetic particle or a chromophore. Thedetectable label may be half of a fluorescence resonance energy transfer(FRET) pair (for FRET variations see, e.g., U.S. Pat. No. 6,593,091,issued to Keys, relevant portions incorporated herein by reference).There are many types of detectable labels, including fluorescent labels,which are easily handled, inexpensive and nontoxic. Another example of adetection method relies on hydrogel-coated donor and acceptor beadsproviding functional groups for conjugation to biomolecules.AlphaScreen® by Berthold Technologies (Bad Wildbad, Germany) (Rouleau,N., Turcotte, S., Mondou, M. H., Roby, P. & Bosse, R. (2003) J BiomolScreen 8, 191-7.).

The present inventors recognized that certain regions of the NS1Aprotein can be targeted for the development of antiviral drugs. The NS1Aprotein is a multi-functional dimeric protein that participates in bothprotein-RNA and protein-protein interactions (Krug et al., 2003). Theeffector domain, which comprises the C-terminal two-thirds of the NS1Aprotein, contains the binding site for the 30-kDa subunit of thecellular cleavage and polyadenylation specificity factor (CPSF30)(Nemeroff et al., 1998; Li et al., 2001). This interaction results inthe inhibition of 3′ end processing of all cellular pre-mRNAs ininfected cells, and as a consequence the production of mature mRNAsencoding antiviral proteins (such as interferon, IFN) is severelyinhibited during infection (Shimizu et al., 1999; Kim et al., 2002; Noahet al., 2003). This inhibition is crucial to viral replication andspread, because influenza A virus, like several other RNA viruses(Yoneyama et al., 2004; Sumpter et al., 2005; Seth et al., 2006),efficiently activates the RIG-I RNA helicase and thereby triggers boththe activation of IRF-3 and NF-kB and the synthesis of IFN-beta andother antiviral pre-mRNAs (Geiss et al., 2002; Kim et al., 2002; Sirenet al., 2006). A recombinant influenza A/Udorn/72 virus expressing aNS1A protein with a mutated binding epitope for CPSF30 induced highlevels of IFN-beta mRNA during infection and was highly attenuated(100-1000-fold) (Noah et al., 2003; Twu et al., 2006). A 61-amino-aciddomain of CPSF30, comprising two of its zinc fingers (i.e., the F2F3fragment), was found to bind efficiently to the NS1A protein (Twu etal., 2006). The expression of the F2F3 domain in cells leads to theinhibition of influenza A virus replication and increased production ofIFN-beta mRNA, indicating that F2F3 likely blocks the binding ofendogenous CPSF30 to the NS1A protein (Twu et al., 2006). These resultsvalidate the binding epitope on NS1A for CPSF30 as a potential targetfor the development of small molecule antiviral drugs directed againstinfluenza A virus and as a target for engineering strains of virus thatcan be used as live attenuated vaccines.

Previous studies showed that residues 184-188 in the protein sequence ofthe NS1A protein are required for functional binding of CPSF30 (Li etal., 2001; Noah et al., 2003). Thus, this region is required for thebinding of CPSF30 in vitro (Li et al., 2001), and mutation of aminoacids 184-188 in the NS1A protein of a recombinant Udorn virus resultsin high attenuation coupled with increased synthesis of IFN-beta (Noahet al., 2003). These data demonstrate that this binding epitope isessential for virus replication. As shown by the structural studiesdescribed below, the 184-188 region of the NS1A protein sequenceconstitutes a subset of the CPSF30 binding epitope, observed in the 3Dstructure of the complex between NS1A effector domain and F2F3 which isdisclosed for the first time in this Disclosure.

Studies with the NS1A proteins of H5N1 viruses established that the Met(M) residue at position 106 is required for functional F2F3/CPSF30binding. We showed that the NS1A protein encoded by a pathogenic H5N1virus that was transmitted to humans in 1997 (A/HK/483/97; HK97) lacks abinding epitope for CPSF30, whereas the NS1A protein encoded by apathogenic 2004 H5N1 virus (A/Vietnam/1203/04; VN04) has acquired thisbinding epitope. We were able to generate a CPSF30 binding epitope inthe HK97 NS1A protein by changing two of its amino acids to thecorresponding amino acids in the VN04 NS1A protein, specifically bychanging I at position 106 to M and L at 103 to F. To determine theeffects of these two amino acid changes in the HK97 NS1A protein duringvirus infection, a recombinant Udorn virus was generated in which theUdorn NS gene was replaced by a HK97 NS gene encoding a NS1A proteinwith these two mutations (Ud/dmHK97 recombinant). The recombinant viruswas then compared to the recombinant Ud virus containing the wild-typeHK97 NS gene (Ud/HK97 recombinant). During multiple cycle growth therate of replication and virus yield of the Ud/dmHK97 recombinant was100-fold greater than with the Ud/HK97 recombinant virus (FIG. 1A), andis thus similar to the Udorn parent virus. During single-cycle growth,the Ud/HK97 virus induced a high level of IFN-beta mRNA production,which was almost completely suppressed in the cells infected by theUd/dmHK97 virus (FIG. 1B). Most importantly, the replication of theUd/dmHK97 virus was inhibited in F2F3-expressing cells (data not shown),indicating that the dmHK97 NS1A protein binds F2F3 in infected cells.The roles of Phe at 103 and the Met at 106 in the NS1A protein informing the F2F3/CPSF30 complex is elucidated by the herein disclosedX-ray crystal structure of the NS1A:F2F3 complex, which reveals thatamino acids 103 and 106 are required for CPSF30 binding because theirhydrophobic interactions stabilize a tetrameric structure of theNS1A:F2F3 complex (see below). It should also be emphasized thatessentially all (>98%) of the influenza A viruses (H3N2, H2N2 and H1N1)that have been isolated from humans, including the 1918 H1N1 virus, andinclude M and F at positions 106 and 103 in their NS1A proteins,respectively, indicating that these two amino acids, which are criticalfor CPSF30 binding and the resulting suppression of the production ofIFN-β mRNA, are conserved in human influenza A viruses. Accordingly, thetetrameric complex described in this disclosure is anticipated to becritical for the CSPF30 binding function of all such human influenza Aviruses.

Example 1 Process for Discovering, Designing, and Optimizing SmallMolecule Inhibitors of Influenza A Viruses, Including H5N1 Viruses

Novel Reagents and Structural Data. To further delineate the interfacebetween F2F3 of CPSF30 and the NS1A protein the inventors determined thethree-dimensional (3D) structure of the tetrameric F2F3:NS1A complex.Ninety (90) different constructs (Table 2) were screened in order tofind constructs suitable for crystallization and NMR analysis. Thesevariants, summarized in Tables 3 and 4, included 8-11 differentfull-length or subsequences of NS1A with N-terminal (N-His) andC-terminal (C-His) affinity purification tags, prepared as described inActon et al., 2005 from influenza A strains A/South Carolina/1/181918(the 1918 pandemic virus H1N1 strain), HK97 (A/HK/483/97, 1997 HongKong), VN04 (A/Vietnam/1203/04, 2005 Vietnam), and Udorn (A/Udorn/72),respectively. These were assessed in terms of expression level andsolubility (Tables 3 and 4), ability to purify, and biophysicalproperties, including 2D ¹⁵N-¹H heteronuclear single quantum coherencecorrelation spectroscopy (HSQC). Many of these reagents, disclosed forthe first time here, are useful for influenza A research purposes andfor structural studies. The inventors focused on two specific constructsthat provide particularly high expression and solubility, making themespecially useful for biochemical and biophysical studies: theC-terminal hexaHis-tagged 85-215 amino acid fragments of the NS1Aproteins from (i) influenza A/Udorn/72 (A/Udorn) and (ii) the H5N1strain A/Vietnam/1203/04 (A/VN04). These highly soluble constructs canbe produced in tens of milligram per liter quantities, and have beenproduced with SeMet labeling, for crystallography, and with¹⁵N-enrichment for NMR studies. Excellent quality HSQC NMR spectra canbe obtained for these two constructs in the pH range 5.5 to 6.5 (FIG.2). Under these conditions, these constructs are of sufficiently goodquality to indicate high feasibility for further NMR studies. They arealso useful for small molecule screening studies. In addition, the F2F3fragment of CPSF30 has been cloned into a pET expression vector with aN-terminal hexaHis tag (tag sequences are defined in Acton et al.,2005), produced with uniform ¹³C, ¹⁵N enrichment, and complete backboneand sidechain resonance assignments have been determined using standardtriple resonance NMR methods (Montelione et al., 1999). TheseNMR-optimized sample conditions and resonance assignments are useful forsmall molecule screening, lead optimization, and structure-functionstudies of F2F3:NS1A interactions.

Because virus studies have used influenza A/Udorn/72 virus to identifyCPSF30 binding activity during virus infection CPSF30 (Li et al., 2001;Noah et al., 2003), we have developed an assay for the binding of theNS1A Udorn effector domain to the F2F3 fragment of CPSF30 in vitro,using analytical gel filtration with detection of effluent bysimultaneous refractive index and static light scattering measurements.The chromatography system used for this assay is described in Acton etal., 2005, in which it is used for other applications. In these studies,illustrated in FIG. 3, the NS1A Udorn (85-215) construct elutes as adimer, with molecular weight of ˜30 kDa. When this effector domainconstruct is first mixed with the 8.5 kDa F3F3 fragment, the resultingcomplex elutes with a molecular weight of ˜50 kDa, indicating astoichiometry of 2 F2F3:2 NS1A effector domains. This gel filtrationassay provides a convenient qualitative measure of F2F3 binding by NS1Aeffector domains.

Suitable samples of NS1A Udorn (85-215); the NS1A-Udorn(85-215):F2F3complex, and other constructs listed in Table 2 and their complexes withF2F3 and CPSF30-derived constructs, can be produced and assessed usingthis gel filtration assay. These can then be crystallized for X-raycrystallographic analysis. Initial crystals of theNS1A-Udorn(85-215):F2F3 complex were obtained by high-throughput roboticscreening using service facilities available through the HauptmanWoodward Res. Inst. (Buffalo N.Y.) (Luft et al., 2003; Acton et al.,2005). Crystallization optimization was then carried out for theNS1A-Udorn(85-215):F2F3 complex at Rutgers, yielding diffraction qualitybi-pyramid crystal of size 0.15×0.15×0.25 mm³. Conditions providingcrystals, and a description of these crystals, are presented hereinbelow. Three-wavelength Se-Met multiple anomalous diffraction (MAD) (2.3Å resolution) and a complete native (1.95 Å resolution) data sets werecollected at X25 beam line at Brookhaven National Laboratories. Thestructure was solved by MAD techniques (Hendrickson, 1991) and refinedto 1.95 Å resolution, and is currently refined to a R factor of 0.225and R free of 0.245, respectively.

Crystallization of NS1A Udorn (85-215):F2F3 Complex. Initialcrystallization conditions for NS1A Udorn (85-215):F2F3 complex wereobtained by using robotic crystallization facility at the Buffalofacility described above. The most promising condition use 1.77 Mpotassium nitrate (KNO₃) at pH 5.0 as precipitant. This initialcrystallization condition was optimized manually at Rutgers. Goodquality crystals were obtained using 0.25-1.0 M KNO₃ and 10-20%sucrose/glucose as precipitant at pH 5-6. Diffraction quality crystalswere obtained when P94S mutant F2F3 was used in the complex, thoughsimilar conditions are expected to provide crystals of the complex withthe wild-type (P94) F2F3 sequence. The NS1A Udorn (85-215):F2F3 complexwas crystallized with the symmetry of the space group P4₁ with cellparameters a=b=50.96, c=205.39 Å and α=β=γ=90°. A variant used in theX-ray crystal structure determination of NS1(85-215):F2F3 complex hasSer in place of Pro at position 94.

FIGS. 4A and 4B disclose the crystal structure of the Udorn NS1Aeffector domain (residues 85-215) bound to the F2F3 fragment of CPSF30.Consistent with gel filtration data, the complex forms a tetramericcomplex, in which two F2F3 molecules bridge two NS1A effector domains.The structure reveals for the first time the novel spatial arrangementof the subunits in the 2 NS1A: 2 F2F3 complex. This tetramericarrangement was completely unexpected and novel.

Key residues Met106/Met106′ of NS1A are packed in the core of thetetrameric interface or “tetramerization epitope,” explaining itscritical role in CPSF30 binding, as discussed above. However, while Met106/Met106′ are at the core of the tetrameric complex, they are not partof the primary F2F3/CPSF30 binding pocket. FIG. 5 illustrates the F2F3binding pocket on the surface the Udorn NS1A effector domain. Specificinteractions in this primary binding pocket involve residues K110, I117,I119, Q121, V180, G183, G184, and W187 of NS1A and residues F97, F98,F103, and K110 of the F3 finger of CPSF30. It should be noted that theseresidues include not only amino acids in, or adjacent to, the 184-188sequence previously identified as part of the CPSF30 binding epitope bymutagenesis studies, but also amino acids in other regions in the NS1Aprotein not previously recognized to be essential for CPSF30 binding.Mutation of residues G183 or G184 in NS1A(85-215) each to Arg or Aspdisrupts or reduces F2F2 binding affinity and/or tetramer formation,based on analytical gel filtration measurements without significantlydisrupting the native structure of NS1A(85-215) indicated by ¹⁵N-¹H HSQCNMR spectra (data not shown), demonstrating a functional role of thesesites within the CPSF30 binding epitope of NS1A. Recombinant Udornviruses encoding NS1A proteins in which either G184 or W187 was changedto Arg are attenuated (data not shown), further demonstrating that theseamino acids are required for virus replication. The eight residues inthe CPSF30-binding epitope of NS1A (FIG. 5) are almost 100% conservedamongst influenza A viruses isolated from humans (Macken et al., 2001),except for Ile117 which is frequently replaced by Met. Based on thisstructure, disclosed for the first time here, we propose disruption of2NS1A:2F2F3 tetramerization as a strategy to inhibit influenza A virusin human. Based on our structural data, we further propose that a smallmolecule inhibitor that binds tightly to the above described conservedepitope and surrounding regions will disrupt CPSF30 binding and willinhibit influenza A virus in humans. This pocket on the surface of theNS1A effector domain is the target of our proposed drug discoveryprocess.

Table 1 describes some of the specific location of the epitopesdescribed herein as the tetramerization, RNA binding and CPSF30 bindingepitopes of NS1A.

TABLE 1 Tetramerization, RNA binding and CPSF30 binding epitopes ofNS1A. NS1A Interacting amino amino acids acids of F2F3 Remark F103 L72,Y88, F103 contributes to both the tetramer interface and the CPSF30-M93, P111 binding epitope F103 interacts with F2 and F3 domains ofCPSF30, may play a role in defining angle between F2 and F3appropriately; mutation of 103 could affect an intermolecular saltbridge between R73 and D125. L105 P111, F112, L105 contributes to boththe tetramer interface and the CPSF30- M124 binding epitope Adjacent toF103 and also interacting at the tetramer (NS1A-2) interface with a2^(nd) NS1A molecule. M106 N107 M106 contributes to both the tetramerinterface and the CPSF30- binding epitope. M106I mutation would effectthe positioning of N107 (of F2F3) and/or Q121 (NS1A same molecule)involved in F2F3- NS1A H-bonds. K110 K110 K110 contributes to theCPSF30-binding epitope. K110 has H-bond with the main-chain carbonyl ofK101 of F2F3. I117 F102 I117 contributes to the CPSF30-binding epitope.Part of the hydrophobic pocket that binds F3 I119 F98, F102 I119contributes to the CPSF30-binding epitope. Part of the hydrophobicpocket that binds F3 Q121 S105, S106 Q121 contributes to theCPSF30-binding epitope. H-bond with amino group of S106 and Oγ of 105(both from CPSF30) D125 R73 D125 contributes to the CPSF30-bindingepitope. Salt bridge with R73 (of CPSF30) L144 No inter- L144 is buriedinto the hydrophobic core of NS1A that probably molecular defines thefold of the protein. A mutation of L144 may alter the shape interactionof NS1A, resulting in reduced CPSF30 and/or dsRNA binding activitiesV180 Y97, K101, V180 contributes to the CPSF30-binding epitope. Part ofthe F3- F102 binding pocket. G183 Y97 G183 contributes to theCPSF30-binding epitope. Part of a helix that forms a wall of theF3-binding pocket. A side-chain may affect (enhance or disrupt) thebinding of F3. G184 Y97, F98 G184 contributes to the CPSF30-bindingepitope. Part of a helix that forms a wall of the F3-binding pocket.Positioned between Y97 and F98 side chains. A mutation of G184 wouldalter the shape of the pocket and can severely affect the binding of F3.W187 C96, Y97, W187 contributes to the CPSF30-binding epitope.Participates in the F98, F112 pocket formation.

Recently, the crystal structure of the NS1A effector domain (residues 79to 205) of the influenza A/PR8/34 (PR8) virus strain was reported(Bornholdt and Prasad, 2006). This PR8 influenza strain is adapted forpassage in mouse, presumably as a result of mouse adaptation, the PR8 NSgene attenuates virus growth in mammalian cells in tissue culture (Ozakiet al, 2004). The PR8 NS1A protein does not bind F2F3 because it lacksthe consensus human sequence at positions 106 (I instead of M) and 103(S instead of F) (Macken et al, 2001), therefore we can determine if theattenuation of growth in mammalian cells is caused primarily by thechanged amino acids at positions 106 and 103 in the PR8 NS1A protein(data not shown). The absence of a CPSF30 binding epitope in the PR8NS1A protein presumably resulted from the large number of passages inmice that have adapted the virus for replication in mice. Consequently,the 3D structure of effector domain of the PR8 NS1A protein (Bornholdtand Prasad, 2006) is not suitable for structure-based drug discoveryefforts. In addition, its structure may differ from that of a NS1Aprotein containing a functional CPSF30 binding epitope. Indeed, the 3Dstructures of the Udorn effector domain monomers in our complex aresimilar to, but not identical with, the structure of the monomers of thePR8 NS1A effector domain structure (FIG. 6). The PR8 NS1A structure doesnot have a F2F3-binding epitope like that observed in the 3D structureof the Udorn NS1A structure described herein. In particular, the PR8NS1A structures lack the hydrophobic pocket that binds F2F3 in theNS1A:F2F3 complex. Moreover, the dimeric interface in crystal structureof the PR8 NS1A effector domain has an intermolecular beta-sheetinteraction (FIG. 7) that is completely different from the interface inthe crystal structure of the Udorn NS1A effector domain bound to F2F3.Therefore, the dimer of the effector domain of the PR8 NS1A protein isnot relevant for the binding of CPSF 30 and to our proposed drug-designstrategy.

Fluorescence polarization (FP) assay. Fluorescence polarization (FP) isa spectroscopic method that measures the rotational rate of a sample insolution. It applies polarized light to excite a fluorophore andmeasures the polarization characteristics of the emitted light (Nasirand Jolley, 1999; Roehrl et al., 2004b). If the sample tumbles slowlycompared to the lifetime of the fluorescence, the emitted light retainssome of the incident polarization. However, if the sample tumbles fast,the emitted light is isotropic. Therefore, the degree of anisotropy(polarization) of the fluorescent light emitted from a sample provides ameasure of the fluorophore's rotational correlation time in the boundstate. Given appropriate bound-state lifetimes, rotational correlationtimes, and changes in rotational correlation upon complex formation, FPassays can be used to measure binding affinities and to screen forbinding inhibitors (Schade et al., 1996; Seethala and Menzel, 1998;Roehrl et al., 2004a).

FP with fluorescently-labeled F2F3. A FP assay of F2F3 binding by NS1Ais being implemented. As mentioned above, complex formation between F2F3and various effector domain constructs is observed in gel filtrationstudies (see FIG. 3), indicating a dissociation constant K_(d) tighterthan low micromolar. These data of FIG. 3 demonstrate the feasibility ofimplementing a FP assay for detecting NS1A:F2F3 binding. Moreover,excellent HSQC spectra and essentially complete NMR resonanceassignments are available for the F2F3 construct (data not shown); thesewill be used to assess the native structural integrity offluorescently-labeled CPSF30 fragments.

In one embodiment of the invention, we will generate a fluorescein (orother fluorophore)—labeled F2F3 (Fluo-F2F3) substrate for FP assay. TheF2F3 sequence of human CPSF30 contains 7 Lys and 6 Cys residues, andfluorophore labeling requires careful consideration to ensure properfolding with Zn ligation by these six Cys residues. Two primarystrategies will be pursued for labeling F2F3: (i) chemical synthesiswith a fluorophore label and (ii) synthesis or biosynthesis of an analogsuitable for specific labeling. The 61-residue F2F3 is sufficientlyshort to allow fluorophore labeling by solid phase peptide synthesis(for example, by a commercial supplier, such as New England Peptide,Inc. Gardner, Mass.). The crystal structure of F2F3 bound to the NS1Aeffector domain indicates that the N-terminal region is not involved inkey binding interactions, and suggests that it may be possible togenerate shorter constructs with similar binding affinities. Thoseconstructs that show tight binding can be synthesized in 100 mg amountsand assayed for structural integrity by ¹⁵N-¹H HSQC NMR analysis atnatural isotopic abundance using a 800 MHz NMR system with cryoprobe.

If for some reason this approach is not successful, fluorophone-labeledF2F3 will be produced by overexpression with a ‘flash’ peptide sequencetag (Griffin et al., 1998; Griffin et al., 2000; Abrams, 2002). When thetetra-cysteine tag [NH₂-Cys-Cys-Pro-Gly-Cys-Cys . . . ] is incorporatedinto proteins/peptides it can be specifically conjugated to abiarsenyl-fluorophore ligand (sold by Invitrogen as theirLumio-technology). The modification can even specifically label thetetra-cysteine tag in vivo (Griffin et al., 2000), and thus should notreact with any of the six cysteine residues on F2F3. If even both ofthese approaches prove to be problematic for this tandem Zn-fingerdomain, alternative strategies for fluorophore labeling are available,such as the method of Ting and colleagues (Chen and Ting, 2005) thatutilizes biotin ligase together with appropriate cofactors to introducefluorescein in a short N-terminal acceptor peptide lacking any Cysresidues, allowing the fluorophore to be introduced subsequent toforming the Zn fingers.

Using any of the above labeling approaches, or other possibleapproaches, the labeled F2F3 can then be folded with Zn ligation usingthe same protocol we have developed for unlabeled F2F3. In exploringeach of these approaches, we will verify that the fluorophore in theN-terminal tag becomes sufficiently immobilized in the complex toprovide a significant change in fluorescence anisotropy. If required, amore immobilized Cys residue within the F2F3 sequence with be introducedwithout interfering with Zn-finger formation, using our 3D structure ofthe NS1A (85-215):F2F3 complex as a guide. Using one of these labelingroutes, or any approach for introducing the fluorescence tag, theresulting FP assay will be validated by measuring competition withunlabeled F2F3.

The crystal structure of the complex between NS1A Udorn(85-215) and theF2F3 CPSF30 reveals that most of the intermolecular interactions betweenNS1A and F2F3 involve the F3 Zn-finger domain (FIG. 5). Accordingly, asmaller flourescein-labeled F3 finger (Fluo-F3), with ˜4 kDa molecularweight, may have preferential properties in developing a FP assay.Though the binding of the NS1A effector domain to Fluo-F3 is likely tobe somewhat weaker than the binding to F2F3, the change in rotationalcorrelation time, and thus the signal-to-noise of the FP assay, will besignificantly higher using Fluo-F3 than using Fluo-F2F3. These designprinciples may be advantageous in development of a high throughput FPassay useful in screening for inhibitors of CPSF30 (or variants,mutants, or fragments thereof) binding to NS1A (or variants, mutants, orfragments thereof).

The crystal structure of the complex between NS1A Udorn (85-215) and theF2F3 fragment further suggests that a tandem repeat of the F2F3fragment, connected by a short flexible linker, F2F3-F2F3, could alsobind in a manner similar to the two independent F2F3 molecules, thoughpotentially with much tighter binding affinity. Accordingly, we willgenerate a variety of F2F3-F2F3 constructs, as outlined below, assaytheir binding, and assess the oligomerization states of these complexesby gel filtration with light scattering detection. If indeed a tandemrepeat F2F3-F2F3 construct can be generated with even tighter bindingthan F2F3 itself, it will be used in a more sensitive FP assay, capableof detecting only more tightly-binding inhibitors.

The magnitude of the change in fluorescence anisotropy, which determinesthe signal-to-noise of the FP assay, depends on the change in rotationalcorrelation time of the fluorophore upon complex formation. If requiredto enhance this change in rotational correlation time, the relative sizeof the NS1A component of NS1A:CSPF30 (or fragments thereof) complexesdescribed above can be further increased by expression as a largerfusion protein (e.g., fused to maltose binding protein), or byattachment to beads or microscopic particles using, for example, alreadyavailable constructs of Tables 2, 3, and 4 with either N- or C-terminalhexHis tags, or using other affinity tags.

Example 2 Constructs to be Used in Developing Fluorescence PolarizationAssay

The crystal structure of the complex between NS1A Udorn (85-215) and theF2F3 fragment was examined to identify potential linking sites so thatthe C-terminus of one segment of F2F3 (or portion thereof) would have afavorable path for linking to the N-terminus of the second segment.Considerations for favorable linking geometry include the distancebetween termini to be linked, the path the linker would need to take,and linker composition and length. A common peptide linker compositionused for connecting domains in engineered proteins is some combinationof Gly and Ser residues, allowing for conformational flexibility andsolubility while remaining somewhat neutral in chemical content, e.g.-Gly-Ser-, or -Gly-Ser-Gly, etc.

Constructs were designed based on the crystal structure of the influenzavirus NS1A-CTD protein complex with the F2F3 fragment from the humanCPSF30 protein, disclosed for this first time in this Disclosure. Theexpectation is that a single-chain construct of the F2F3 binding regionsobserved in the crystal structure would bind more tightly to the NS1Adimer than the separate domains, and might have significant antiviralactivity.

The structure was examined to identify potential linking sites so thatthe C-terminus of one segment of F2F3 (or portion thereof) would have afavorable path for linking to the N-terminus of the second segment.Considerations for favorable linking geometry include the distancebetween termini to be linked, the path the linker would need to take,and linker composition and length. A common peptide linker compositionused for connecting domains in engineered proteins is some combinationof Gly and Ser residues, allowing for conformational flexibility andsolubility while remaining somewhat neutral in chemical content, e.g.-Gly-Ser-, or -Gly-Ser-Gly, etc.

The sequence of CPSF30 F2F3 used for the specific designs is that usedin the crystal structure determination, but amino acid replacements canbe considered. The N-terminal portion might include a hexa-His or othertag for convenient purification; alternatively a tag might be encoded atthe C-terminus of the construct. Other purification tags may bepreferable to oligo-His owing to potential interference with thechelation of zinc ions by the F2 and F3 “Zn finger” segments, which isrequired for the integrity of the three-dimensional structure and foreffective binding to NS1A. In all of these F2F3 sequences, residue Pro92may be substituted by Ser. The constructs involving single F3 domains(“one finger”) as opposed to F2F3 domains (“two fingers”) arepotentially valuable as minimal/miniature versions because theinteraction between separate F2F3 chains in the dimer (chains F2F3-A andF2F3-B) is mediated entirely by residues in F3 and does not involve anyresidues from F2. The F3 domain itself, or variants, could be used as anantiviral drug.

Relatively few of the residues in F2 make important interactions withthe NS1A protein in the dimer of dimers; notable exceptions are Leu72and Arg73, whose side chains interact extensively with NS1A. The Leu72and Arg73 interactions could be maintained by a strategic linkage of aLeu-Arg or Arg-Leu peptide to Thr91 (proposed N-terminus of the F3domain construct). L72-T91 distance is 14.2 Å; R73-T91 distance is 17.6Å. Possible extensions to the one-finger F3 domain construct would beLeu-Arg-GSGSG-F3 or Arg-Leu-GSGSG-F3 (see proposed constructs 5a and5b).

F2F3 sequence (numbered as in human CPSF30 protein):

(SEQ ID NO.: 2)61           71         81         91         101        111M SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKMPECYFYS KFGECSNKEC PFLHIDPESK I

Construct 1. F3-F3: Single F3-linker-F3 construct (tandem F3 construct)(abbreviated: (91-116)-linker(11+)-(91-116)). Distance from F2F3-AAsp116 Ca to F2F3-B Thr91 Ca is 33.3 Å; linker can be 10+ flexible aminoacids;

11: -GSGSGSGSGSG- also written as -(GS)₅G-; (SEQ ID NO.: 3)13: -GSGSGSGSGSGSG- also written as -(GS)₆G-; (SEQ ID NO.: 4)91         101        111      linker   91         101        111   116TKMPECYFYS KFGECSNKEC PFLHID - (GS)_(N)G - TKMPECYFYS KFGECSNKEC PFLHID(SEQ ID NO.: 5)

C-terminal residue of tandem construct can be D116 or any extension upto 1121; crystal structure extends only to P117 in one copy and E118 inthe other. Both N- and C-termini can have extensions including hexaHisand other tags for convenient purification as discussed in the text.

Construct 2. F2F3-F3: Same as previous construct except that theN-terminal portion of the construct encompasses entire F2F3 segment(abbreviated) (60-116)-linker(11+)-(91-116):

(SEQ ID NO.: 6)61           71         81         91        101         111M SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKMPECYFYS KFGECSNKEC PFLHID -linker   91         101        111   116(GS)_(N)G - TKMPECYFYS KFGECSNKEC PFLHID

Construct 3. F2F3-F2F3: F2F3-linker-F2F3 construct (tandem F2F3construct) (abbreviated: (60-116)-linker(15+)-(62-116)). Distance fromF2F3-A Asp116 Ca to F2F3-B Gly62 Ca is 51.1 Å; linker should be 14+flexible amino acids:

15: -GSGSGSGSGSGSGSG- also written as -(GS)₇G-; (SEQ ID NO.: 7)17: -GSGSGSGSGSGSGSGSG- also written as -(GS)₈G-; (SEQ ID NO.: 8)61    71           81      91         101         111M SGEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKMPECYFYS KFGECSNKEC PFLHID -linker   62        71         81         91         101        111(GS)_(N)G - GEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKMPECYFYS KFGECSNKEC PFLHID.(SEQ ID NO.: 9)

Construct 4. F3-F2F3: F3-linker-F2F3 construct (abbreviated:(91-116)-linker(15+)-(62-116)). Distance from F2F3-A Asp116 Ca to F2F3-BGly62 Ca is 51.1 Å; linker should be 14+ flexible amino acids.

(SEQ ID NO.: 10) 91         101        111  116  linkerTKMPECYFYS KFGECSNKEC PFLHID - (GS)_(N)G -62        71         81         91         101        111GEKTVVCKH WLRGLCKKGD QCEFLHEYDM TKMPECYFYS KFGECSNKEC PFLHID

Construct 5. XF3-F3: Extended F3-linker-F3 construct. Linker 1 will linka Leu-Arg or Arg-Leu dipeptide to the one-finger F3 domain in a mode toincorporate the important L72 and R73 side-chain interactions from F2that are otherwise missing. Linker 2 can be 10+ flexible amino acids:

Construct 5a (abbreviated:Leu-Arg-linker(5+)-(91-116)-linker(11+)-(91-116)):

(SEQ ID NO.: 11)72  73  linker 1  91          101       111 116  linker 2Leu-Arg - GSGSG - TKMPECYFYS KFGECSNKEC PFLHID - (GS)_(N)G -91         101        111 116 TKMPECYFYS KFGECSNKEC PFLHID

Construct 5b (abbreviated:Arg-Leu-linker(5+)-(91-116)-linker(11+)-(91-116)):

(SEQ ID NO.: 12)73  72  linker 1  91        101         111  116  linker 2Arg-Leu - GSGSG - TKMPECYFYS KFGECSNKEC PFLHID - (GS)_(N)G -91         101        111 116 TKMPECYFYS KFGECSNKEC PFLHID

Each of the constructs 1-5b above, and variants thereof, will inhibitCPSF30 binding by NS1A, and can potentially be used as lead compoundsfor drug development and/or as antiviral drugs useful in preventing ortreating influenza A infection in humans, poultry (e.g. chicken), andother animals.

Structure-based Lead Optimization using X-ray Crystallography and NMR.The sample preparation and structural characterization of NS1A effectordomains from multiple influenza strains, allow the use of both NMR andX-ray crystallography in hit validation, lead compound optimization, anddrug discovery.

Crystallography for lead optimization. X-ray analysis has historicallybeen very important to structure-based inhibitor design. Compoundsidentified as inhibitor “hits” by kinetic assays can be used to formcomplexes with the target protein. X-ray analysis will reveal the modeof inhibitor binding and act as a basis for further inhibitor design.Crystal inhibitor complexes can also be formed by soaking inhibitorsinto preformed crystals, or complexes may be grown byco-crystallization. The latter case may be necessary if the complextriggers conformational changes. In either case, diffraction data iscollected on a rotating anode source, processed, and converted toelectron density maps. The orientation and occupancy of the inhibitorswill be observed and compared with binding modes predicted from virtualscreening or models from earlier design cycles. In this way, inhibitorsanalyzed in one cycle of design will feed into subsequent rounds ofstructural analysis and re-design in the general process ofstructure-based drug design (Kuhn 2002; Scapin 2006)

Cocrystallization and Crystal soaks. Using crystallization conditionsthat we have already optimized for the NS1A effector domains, describedabove, cocrystallizations and crystal soaks can be carried out with leadcompounds identified in our high throughput screening efforts. Trialswill be carried out to crystallize NS1A effector domain:lead compoundcomplexes. Diffraction data can be collected using either home orsynchrotron X-ray sources and the resulting difference electron densitymaps and 3D structures can be used to characterize small moleculebinding epitopes and bound-state conformations. These data can be usedscreening for lead compounds either one at a time or in high throughputformat, lead compound validation, and optimization of lead compounds,using methods familiar to a person skilled in the art.

NMR for lead identification optimization. NMR is also a powerful methodfor validating intermolecular interactions, and is used extensively incommercial pharmaceutical drug discovery efforts to identify leadcompounds and their protein binding sites (Shuker et al., 1996; Hajduket al., 1997; Moore, 1999a, 1999b; Muegge et al., 1999; Moy et al.,2001; Powers, 2002; Lepre et al., 2004; Rush and Powers, 2004; Mercieret al., 2006; Petros et al., 2006). NMR chemical shift perturbations, ofeither the protein or the ligand, can be used for screening for smallmolecule lead compounds, validating initial small molecule hitsidentified with htp or virtual screening assays, locating thecorresponding binding site in the 3D protein structure, and to guiderational lead optimization. NMR methods uniquely complementcrystallography studies. Strengths of NMR analysis methods include (i)the ability to detect even weak (K_(d) up to ˜500 micromolar) bindinginteractions, (ii) compatibility with systems that undergo structuralchanges upon ligand binding which may not be accommodated by acrystalline lattice, (iii) the ability to adjust solvent conditions overa wide range, and (iv) high sensitivity and very low samplerequirements.

Using NS1A effector domain constructs that have already been shown toprovide high quality HSQC spectra (e.g., FIG. 2), NMR chemical shiftperturbation can be used to validate initial small molecule hitsidentified with high-throughput (htp) or virtual screening assays,locating the corresponding binding site in the 3D protein structure, andfor rational lead optimization. Hits identified in htp FP assays will becharacterized by assessing perturbations in HSQC spectra for whichresonance assignments will be available, and interpreting these effectson the available 3D structures of NS1 effector domains. Some methodssuitable for lead compound screening, identification, and optimizationenvisioned for use with our invention are summarized in C. A. Lepre, J.M, Moore, and J. W. Peng, Theory and Applications of NMR-based Screeningin Pharmaceutical Research (Chem. Rev. 104, 3641-3675 (2004)), which isincorporated herein by reference. The NMR infrastructure required forsuch work are available at most large research institutions, includingby not limited to Rutgers University, and include 5 mm 600 and 800 MHzNMR cryoprobe systems, as well as a 1 mm 600 MHz NMR equipped with anautomated sample changer. The cryoprobes enable recording ofhigh-quality HSQC data using 150 microliter samples at proteinconcentrations as low as 10 micromolar, and the 1 mm NMR probe provideshigh quality HSQC data on 7 microliter samples at 100 micromolarconcentrations. Such NMR technologies allow NMR screening for leadcompound optimization with as little as ˜500 nanomoles of each sample.Where appropriate, the 3D structures of tightly bound small moleculelead compounds may also be determined by NMR methods if they cannot besolved by crystallographic methods. These data will be used in redesignand lead optimization as outlined for crystallographic data above.

Expressed soluble constructs of NS1A outlined in Tables 2, 3 and 4, ortheir variants, can also be used to screen for small molecule leadcompounds using NMR detection of resonances of the small molecule, usinglimits described by (but not limited to) C. A. Lepre, J. M, Moore, andJ. W. Peng, Theory and Applications of NMR-based Screening inPharmaceutical Research (Chem. Rev. 104, 3641-3675 (2004)).

Where appropriate, the 3D structures of tightly bound small moleculelead compounds may also be determined by NMR methods if they cannot besolved by crystallographic methods. These data will be used in redesignand lead optimization using synthetic chemistry, as outlined forcrystallographic data above.

Antiviral assays. Having identified inhibitors of the interactionbetween NS1A and CPSF30, the inhibitors would be tested for theirability to inhibit influenza A virus replication in tissue culturestudies. Plaque reduction assays in MDCK cells will be used to assaycompounds for their ability to inhibit influenza A virus replication(Twu et al., 2006). Monolayers of MDCK cells will be infected withapproximately 100 plaque-forming units (PFU) of influenza A/Udorn/72virus, and after virus adsorption the cells will be overlaid with agarcontaining a concentration of a compound ranging from 0.001micrograms/ml to 10 micrograms/ml. Plaques will be counted in duplicateplates and compared to the number of plaques in controls not exposed tothe chemical. In parallel cytotoxicity evaluations of lead compoundswould be carried out on MDCK cells using the Roche reagent WST-1(Berridge et al., 2005). The rate of WST-1 cleavage by mitochondrialdehydrogenases, yielding a product with absorbance at 450 nm, correlateswith the number of viable cells. These assays will be carried out in96-well tissue culture plates, and cell viability will be assayed bydetermining absorbance at 450 nm using an ELISA plate reader. Once themost promising lead compounds with low cytotoxicity in both MDCK andhuman (A549) cells have been identified, we will determine the effect ofseveral concentrations of the compounds on the rate and extent of virusreplication during multiple-cycle growth in MDCK cells. The compoundswith the greatest inhibitory activity at the lowest concentrations willbe used for subsequent studies in a suitable animal model (ferrets).

Applications of NS1A:CPSF30 Inhibitors. These inhibitors can bedeveloped into antiviral drugs that will be effective in the control ofinfluenza virus epidemics and pandemics in humans. Because there is thepotential for such epidemics to be man-made, i.e., using influenza Avirus as a bioterrorist weapon, such antivirals would also be crucial inthis situation. Influenza antiviral drugs will also be important for thecontrol of influenza A infections in commercial poultry stocks, such aschickens.

TABLE 2 pET-based vectors for NS1A proteins and fragments from variousflu strains. 1918 HK97 VN04 Udorn Full-length N-His and C-His N-His andC-His N-His and C-His N-His and C-His  1-215 N-His and C-His N-His andC-His N-His and C-His N-His and C-His 73-215 N-His and C-His N-His andC-His N-His and C-His N-His and C-His 85-215 N-His and C-His N-His andC-His N-His and C-His N-His and C-His 91-215 C-His Not attempted C-HisC-His  1-211 N-His and C-His N-His and C-His N-His and C-His N-His andC-His 85-211 N-His and C-His N-His and C-His N-His and C-His N-His andC-His 73-211 N-His and C-His N-His and C-His N-His and C-His N-His andC-His 91-211 C-His Not attempted Not attempted Not attempted 85-204C-His C-His C-His C-His 91-204 C-His Not attempted C-His C-His

TABLE 3 N-terminal His tag NS1 Expression/Solubility results for NS1Aproteins and fragments from various flu strains. 1918 HK97 VN04 Udorn FLyes/low yes/low no/na yes/low  1-215 yes/low yes/low yes/no yes/low73-215 yes/no yes/med yes/no yes/low 85-215 yes/low yes/low yes/lowyes/med  1-211 yes/no yes/low yes/no yes/low 85-211 yes/low yes/noyes/med yes/med 73-211 yes/low yes/no yes/med yes/low

TABLE 4 C-terminal His tag NS1 Expression/Solubility results for NS1Aproteins and fragments from various flu strains. 1918 HK97 VN04 Udorn FLyes/low yes/no no/na yes/low  1-215 yes/no yes/medium yes/no yes/no73-215 na na yes/no yes/low 85-215 yes/medium yes/good yes/low yes/low91-215 yes/low yes/low na yes/low  1-211 no/na na yes/no na 85-211yes/no yes/no yes/low yes/no 73-211 na yes/no yes/good yes/no 91-211yes/no na na na 85-204 yes/low yes/low yes/low yes/low 91-204 yes/noyes/no na yes/no

Creating Attenuated Influenza Virus Strains Suitable for Avian and HumanInfluenza Vaccine Development. The structural information disclosed herecan be combined with site-directed mutagenesis data for NS1A to engineerattenuated influenza A virus strains suitable for use as live attenuatedvaccines in humans and livestock. Multiple, weakly attenuating mutationswill be created in the CPSF30 and dsRNA-binding epitopes to generate NS1proteins with reduced binding affinity in vitro. The effects of thesemutations on the structural integrity of NS1A variants can be assessedwith HSQC NMR data and/or crystallization and X-ray crystallography.These data will then be used to engineer viral strains of influenza Awith various degrees of attenuation. These viral strains will beengineered to contain multiple base changes to minimize the potential ofthe virus to revert to virulence. Such influenza A viruses would beattenuated in normal cells, and in humans and animals, but would not beattenuated in cells lacking interferon genes (e.g. cell culture Verocells), thereby enabling the production of large amounts of theseattenuated viruses suitable for use as a live virus vaccine.

Methods for development of attenuated flu vaccines are described in U.S.Provisional Patent Application Ser. No. 60/737,742, “Novel Compositionsand Vaccines Against Influenza and Influenza B Infections,”, and PTCPatent Application Filed Nov. 17, 2006 “Novel Compositions and VaccinesAgainst Influenza and Influenza B Infections,” relevant portions andtables incorporated herein by reference, relevant portions incorporatedherein by reference.

A person of ordinary skill in the art will understand that because ofthe degeneracy of the genetic code, a large number of nucleic acidsequences can be generated in accordance with this invention. Theproduction of the viruses of the instant invention (or the respectiverecombinant NS1A protein or respective NS1B protein comprising saidamino acid sequences) can be achieved by recombinant DNA technology.Nucleic acid sequences encoding the amino acid sequences of the instantinvention can be produced using methods well known in the art,including, for example, chemical synthesis, PCR and site-directedmutagenesis.

The instant invention provides recombinant influenza A virus comprisingthe amino acid sequences which are at least 70% identical but less than100% identical either to dsRNA binding domains of NS1A. These virusesmay be generated, for example, by reverse genetic system, wherebyinfluenza virus can be generated by transfection of multiple DNAswithout a helper virus. This technique was described in Fodor et al.,1999. Essentially, in that study the technique involved transfectinginto a host cell a combination of plasmids containing cDNAs for theviral RNA segments (including NS1 proteins), proteins of viral RNAdependent polymerase complex (PB1, PB2, and PA), and nucleoprotein.Further, it is possible to transfect host cells (such as, for example293 cells or Vero cells) with a plasmid encoding a recombinant NS1Aprotein (for rescuing influenza A viral phenotype) containing theappropriate amino acid sequence of the instant invention. The resultingviruses may be used for creation of vaccines, as described below.

In another embodiment, the virus can be propagated in suitable host,such as, for example, chicken eggs, without a need for transforming ahost cell with multiple plasmids. In this embodiment, essentially,clinical isolates of human influenza virus are taken from infectedpatients and are reassorted in embryonated chicken eggs withlaboratory-adapted master strains of high-growth donor viruses.

To prepare the recombinant NS1A viruses for different purposes(including, without limitations, the use of the virus as a vaccine or apart thereof), each of these mutations may be carried out individuallyon constructs of NS 1A suitable for biochemical characterization,possibly including but not limited to the constructs outlined in Tables3 and 4. Other variants of NS1A or affinity tags (e.g. FLAG tags) mayalso be used. These proteins may be purified and characterized withrespect to structural integrity by comparing the circular dichroismand/or NMR spectrum and/or X-ray crystal structures with those of thecorresponding wild-type NS1 construct. The several constructs may thenbe assayed for dsRNA binding as described elsewhere (Chien et al.,2004), or using other methods of assessing protein-dsRNA bindingaffinities commonly used for such studies, such as, for example,sedimentation equilibrium, gel electrophoresis, or gel filtrationchromatography. These data will be used to assess the effect of singlesite mutants at these sites revealed by the structural models to beimportant for dsRNA recognition. Further, sets of double, triple, andquadruple mutants of residues in the CPSF30 binding epitope, tetramerinterface, dsRNA binding epitope, and combinations thereof would also begenerated in these NS1A constructs and assessed for structural integrityand binding activities in vitro. This experimental design will allow aperson of the ordinary skill in the art to identify mutant forms of NS1Aand NS1A varients with minimal structural disruption but with reducedCPSF30 and/or dsRNA binding affinity.

The invention encompasses methods of selecting viruses which have thedesired phenotype, i.e., viruses which have low or no dsRNA bindingactivity, whether obtained from natural variants, spontaneous variants(i.e., variants which evolve during virus propagation), mutagenizednatural variants, reassortants and/or genetically engineered viruses.Such viruses can be best screened in differential growth assays thatcompare growth in host systems which have attenuated and normal immuneresponse to influenza A viruses. Viruses which demonstrate better growthin the hosts having the attenuated response versus the normal responseare selected; preferably, viruses which grow to titers at least one loggreater in the host systems with the attenuated response as compared tothe host system with the normal response are selected.

The present invention also encompasses methods of growing and isolatingmutated viruses having altered dsRNA binding activity in cells and celllines which naturally exhibit an attenuated response to viral infectionsas compared to wild-type cells. In a particular preferred embodiment,the present invention relates to methods of growing the viruses of theinstant invention in Vero cells.

It is contemplated that any embodiment discussed in this specificationcan be implemented with respect to any method, kit, reagent, orcomposition of the invention, and vice versa. Furthermore, compositionsof the invention can be used to achieve methods of the invention.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All publications and patent applications mentioned in the specificationare indicative of the level of skill of those skilled in the art towhich this invention pertains. All publications and patent applicationsare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The use of the word “a” or “an” when used in conjunction with the term“comprising” in the claims and/or the specification may mean “one,” butit is also consistent with the meaning of “one or more,” “at least one,”and “one or more than one.” The use of the term “or” in the claims isused to mean “and/or” unless explicitly indicated to refer toalternatives only or the alternatives are mutually exclusive, althoughthe disclosure supports a definition that refers to only alternativesand “and/or.” Throughout this application, the term “about” is used toindicate that a value includes the inherent variation of error for thedevice, the method being employed to determine the value, or thevariation that exists among the study subjects.

As used in this specification and claim(s), the words “comprising” (andany form of comprising, such as “comprise” and “comprises”), “having”(and any form of having, such as “have” and “has”), “including” (and anyform of including, such as “includes” and “include”) or “containing”(and any form of containing, such as “contains” and “contain”) areinclusive or open-ended and do not exclude additional, unrecitedelements or method steps.

The term “or combinations thereof” as used herein refers to allpermutations and combinations of the listed items preceding the term.For example, “A, B, C, or combinations thereof” is intended to includeat least one of: A, B, C, AB, AC, BC, or ABC, and if order is importantin a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.Continuing with this example, expressly included are combinations thatcontain repeats of one or more item or term, such as BB, AAA, AB, BBC,AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan willunderstand that typically there is no limit on the number of items orterms in any combination, unless otherwise apparent from the context.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims.

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HEADER −−−− XX−XXX−XX xxxx COMPND −−− REMARK 3 REMARK 3 REFINEMENT.REMARK 3 PROGRAM: REFMAC 5.2.0005 REMARK 3 AUTHORS: MURSHUDOV, VAGIN,DODSON REMARK 3 REMARK 3 REFINEMENT TARGET: MAXIMUM LIKELIHOOD REMARK 3REMARK 3 DATA USED IN REFINEMENT. REMARK 3 RESOLUTION RANGE HIGH(ANGSTROMS): 1.95 REMARK 3 RESOLUTION RANGE LOW (ANGSTROMS): 25.00REMARK 3 DATA CUTOFF (SIGMA(F)): NONE REMARK 3 COMPLETENESS FOR RANGE(%): 97.88 REMARK 3 NUMBER OF REFLECTIONS: 35935 REMARK 3 REMARK 3 FITTO DATA USED IN REFINEMENT. REMARK 3 CROSS−VALIDATION METHOD: THROUGHOUTREMARK 3 FREE R VALUE TEST SET SELECTION: RANDOM REMARK 3 R VALUE(WORKING + TEST SET): 0.19912 REMARK 3 R VALUE (WORKING SET): 0.19794REMARK 3 FREE R VALUE: 0.23607 REMARK 3 FREE R VALUE TEST SET SIZE (%):3.1 REMARK 3 FREE R VALUE TEST SET COUNT: 1159 REMARK 3 REMARK 3 FIT INTHE HIGHEST RESOLUTION BIN. REMARK 3 TOTAL NUMBER OF BINS USED: 20REMARK 3 BIN RESOLUTION RANGE HIGH: 1.950 REMARK 3 BIN RESOLUTION RANGELOW: 2.000 REMARK 3 REFLECTION IN BIN (WORKING SET): 2372 REMARK 3 BINCOMPLETENESS (WORKING(%): 87.48 REMARK 3 BIN R VALUE (WORKING SET):0.251 REMARK 3 BIN FREE R VALUE SET COUNT: 66 REMARK 3 BIN FREE R VALUE:0.310 REMARK 3 REMARK 3 NUMBER OF NON−HYDROGEN ATOMS USED IN REFINEMENT.REMARK 3 ALL ATOMS: 3121 REMARK 3 REMARK 3 B VALUES. REMARK 3 FROMWILSON PLOT (A**2): NULL REMARK 3 MEAN B VALUE (OVERALL, A**2): 36.438REMARK 3 OVERALL ANISOTROPIC B VALUE. REMARK 3 B11 (A**2): 1.36 REMARK 3B22 (A**2): 1.36 REMARK 3 B33 (A**2): −2.71 REMARK 3 B12 (A**2): 0.00REMARK 3 B13 (A**2): 0.00 REMARK 3 B23 (A**2): 0.00 REMARK 3 REMARK 3ESTIMATED OVERALL COORDINATE ERROR. REMARK 3 ESU BASED ON R VALUE (A):0.143 REMARK 3 ESU BASED ON FREE R VALUE (A): 0.138 REMARK 3 ESU BASEDON MAXIMUM LIKELIHOOD (A): 0.102 REMARK 3 ESU FOR B VALUES BASED ONMAXIMUM LIKELIHOOD (A**2): 3.568 REMARK 3 REMARK 3 CORRELATIONCOEFFICIENTS. REMARK 3 CORRELATION COEFFICIENT FO−FC: 0.956 REMARK 3CORRELATION COEFFICIENT FO−FC FREE: 0.942 REMARK 3 REMARK 3 RMSDEVIATIONS FROM IDEAL VALUES COUNT RMS WEIGHT REMARK 3 BOND LENGTHSREFINED ATOMS (A): 2997 ; 0.020 ; 0.022 REMARK 3 BOND ANGLES REFINEDATOMS 4042 ; 1.715 ; 1.956 (DEGREES): REMARK 3 TORSION ANGLES, PERIOD 1(DEGREES): 357 ; 6.180 ; 5.000 REMARK 3 TORSION ANGLES, PERIOD 2(DEGREES): 137 ; 34.186 ; 24.015 REMARK 3 TORSION ANGLES, PERIOD 3(DEGREES): 548 ; 14.846 ; 15.000 REMARK 3 TORSION ANGLES, PERIOD 4(DEGREES): 16 ; 17.200 ; 15.000 REMARK 3 CHIRAL- CENTER RESTRAINTS(A**3): 435 ; 0.126 ; 0.200 REMARK 3 GENERAL PLANES REFINED ATOMS (A):2240 ; 0.007 ; 0.020 REMARK 3 NON-BONDED CONTACTS REFINED 1262 ; 0.212 ;0.200 ATOMS (A): REMARK 3 NON- BONDED TORSION REFINED 2012 ; 0.311 ;0.200 ATOMS (A): REMARK 3 H- BOND (X...Y) REFINED ATOMS (A): 162 ; 0.165; 0.200 REMARK 3 POTENTIAL METAL−ION REFINED 1 ; 0.109 ; 0.200 ATOMS(A): REMARK 3 SYMMETRY VDW REFINED ATOMS (A): 85 ; 0.232 ; 0.200 REMARK3 SYMMETRY H−BOND REFINED 14 ; 0.182 ; 0.200 ATOMS (A): REMARK 3 REMARK3 ISOTROPIC THERMAL FACTOR COUNT RMS WEIGHT RESTRAINTS. REMARK 3 MAIN-CHAIN BOND REFINED ATOMS 1889 ; 1.376 ; 1.500 (A**2): REMARK 3 MAIN-CHAIN ANGLE REFINED ATOMS 2920 ; 2.197 ; 2.000 (A**2): REMARK 3 SIDE-CHAIN BOND REFINED ATOMS 1300 ; 2.913 ; 3.000 (A**2): REMARK 3 SIDE-CHAIN ANGLE REFINED ATOMS 1122 ; 4.495 ; 4.500 (A**2): REMARK 3 REMARK 3NCS RESTRAINTS STATISTICS REMARK 3 NUMBER OF NCS GROUPS: NULL REMARK 3REMARK 3 REMARK 3 TLS DETAILS REMARK 3 NUMBER OF TLS GROUPS: NULL REMARK3 REMARK 3 REMARK 3 BULK SOLVENT MODELLING. REMARK 3 METHOD USED: MASKREMARK 3 PARAMETERS FOR MASK CALCULATION REMARK 3 VDW PROBE RADIUS: 1.20REMARK 3 ION PROBE RADIUS: 0.80 REMARK 3 SHRINKAGE RADIUS: 0.80 REMARK 3REMARK 3 OTHER REFINEMENT REMARKS: REMARK 3 HYDROGENS HAVE BEEN ADDED INTHE RIDING POSITIONS REMARK 3 CRYST1 50.961 50.961 205.387 90.00 90.0090.00 P 41 SCALE1 0.019623 0.000000 0.000000 0.00000 SCALE2 0.0000000.019623 0.000000 0.00000 SCALE3 0.000000 0.000000 0.004869 0.00000 ATOM1 N PRO A 85 −26.122 32.840 39.164 1.00 67.70 N ATOM 2 CA PRO A 85−26.884 33.641 38.196 1.00 67.41 C ATOM 3 CB PRO A 85 −26.347 35.07138.415 1.00 67.69 C ATOM 4 CG PRO A 85 −25.675 35.066 39.826 1.00 68.21C ATOM 5 CD PRO A 85 −25.736 33.625 40.355 1.00 68.25 C ATOM 6 C PRO A85 −26.665 33.197 36.735 1.00 66.66 C ATOM 7 O PRO A 85 −25.599 32.63636.413 1.00 67.05 O ATOM 8 N ALA A 86 −27.666 33.441 35.876 1.00 65.01 NATOM 9 CA ALA A 86 −27.562 33.211 34.427 1.00 63.22 C ATOM 10 CB ALA A86 −28.909 33.479 33.746 1.00 63.77 C ATOM 11 C ALA A 86 −26.438 34.04933.773 1.00 61.60 C ATOM 12 O ALA A 86 −26.536 35.280 33.715 1.00 61.58O ATOM 13 N SER A 87 −25.385 33.361 33.294 1.00 59.11 N ATOM 14 CA SER A87 −24.164 33.987 32.734 1.00 56.32 C ATOM 15 CB SER A 87 −23.014 32.96832.609 1.00 56.60 C ATOM 16 OG SER A 87 −22.933 32.092 33.722 1.00 55.71O ATOM 17 C SER A 87 −24.439 34.600 31.365 1.00 54.09 C ATOM 18 O SER A87 −25.441 34.273 30.727 1.00 53.42 O ATOM 19 N ARG A 88 −23.560 35.50730.928 1.00 51.11 N ATOM 20 CA ARG A 88 −23.691 36.103 29.599 1.00 49.05C ATOM 21 CB ARG A 88 −22.704 37.255 29.435 1.00 49.01 C ATOM 22 CG ARGA 88 −23.079 38.587 30.081 1.00 52.03 C ATOM 23 CD ARG A 88 −21.92139.576 29.841 1.00 51.77 C ATOM 24 NE ARG A 88 −21.495 39.538 28.4371.00 56.44 N ATOM 25 CZ ARG A 88 −20.325 39.972 27.964 1.00 56.82 C ATOM26 NH1 ARG A 88 −19.396 40.504 28.770 1.00 52.97 N ATOM 27 NH2 ARG A 88−20.093 39.853 26.662 1.00 58.69 N ATOM 28 C ARG A 88 −23.391 35.05628.527 1.00 45.17 C ATOM 29 O ARG A 88 −22.545 34.198 28.745 1.00 43.46O ATOM 30 N TYR A 89 −24.092 35.139 27.399 1.00 42.80 N ATOM 31 CA TYR A89 −23.763 34.336 26.204 1.00 42.12 C ATOM 32 CB TYR A 89 −24.984 33.63925.610 1.00 43.89 C ATOM 33 CG TYR A 89 −25.584 32.586 26.481 1.00 49.25C ATOM 34 CD1 TYR A 89 −26.692 32.877 27.301 1.00 53.80 C ATOM 35 CE1TYR A 89 −27.278 31.876 28.129 1.00 55.07 C ATOM 36 CZ TYR A 89 −26.74530.583 28.120 1.00 53.29 C ATOM 37 OH TYR A 89 −27.307 29.603 28.9241.00 52.63 O ATOM 38 CE2 TYR A 89 −25.633 30.272 27.320 1.00 52.65 CATOM 39 CD2 TYR A 89 −25.059 31.275 26.501 1.00 51.55 C ATOM 40 C TYR A89 −23.103 35.144 25.095 1.00 39.05 C ATOM 41 O TYR A 89 −23.578 36.22224.734 1.00 39.30 O ATOM 42 N ILE A 90 −22.007 34.604 24.565 1.00 35.95N ATOM 43 CA ILE A 90 −21.374 35.101 23.343 1.00 33.00 C ATOM 44 CB ILEA 90 −19.815 35.017 23.400 1.00 33.20 C ATOM 45 CG1 ILE A 90 −19.21335.693 24.659 1.00 31.66 C ATOM 46 CD1 ILE A 90 −19.623 37.181 24.9461.00 34.93 C ATOM 47 CG2 ILE A 90 −19.218 35.494 22.065 1.00 32.68 CATOM 48 C ILE A 90 −21.815 34.214 22.179 1.00 31.70 C ATOM 49 O ILE A 90−21.772 32.988 22.277 1.00 30.65 O ATOM 50 N THR A 91 −22.206 34.84821.084 1.00 30.72 N ATOM 51 CA THR A 91 −22.721 34.177 19.892 1.00 30.64C ATOM 52 CB THR A 91 −24.272 34.313 19.747 1.00 30.93 C ATOM 53 OG1 THRA 91 −24.641 35.693 19.595 1.00 31.58 O ATOM 54 CG2 THR A 91 −25.01033.726 20.961 1.00 31.12 C ATOM 55 C THR A 91 −21.973 34.698 18.654 1.0030.39 C ATOM 56 O THR A 91 −22.425 35.616 18.014 1.00 29.92 O ATOM 57 NASP A 92 −20.789 34.150 18.367 1.00 29.53 N ATOM 58 CA ASP A 92 −20.08834.437 17.103 1.00 29.38 C ATOM 59 CB ASP A 92 −18.705 33.737 16.9871.00 29.06 C ATOM 60 CG ASP A 92 −17.630 34.283 17.934 1.00 30.61 C ATOM61 OD1 ASP A 92 −17.802 35.375 18.537 1.00 29.26 O ATOM 62 OD2 ASP A 92−16.577 33.585 18.121 1.00 25.92 O ATOM 63 C ASP A 92 −20.917 33.92015.919 1.00 29.87 C ATOM 64 O ASP A 92 −20.852 34.518 14.848 1.00 30.63O ATOM 65 N MET A 93 −21.646 32.798 16.090 1.00 28.80 N ATOM 66 CA MET A93 −22.334 32.178 14.985 1.00 28.53 C ATOM 67 CB MET A 93 −22.254 30.62515.045 1.00 28.56 C ATOM 68 CG MET A 93 −20.873 30.056 14.617 1.00 23.17C ATOM 69 SD MET A 93 −20.816 28.244 14.793 1.00 22.81 S ATOM 70 CE META 93 −20.351 28.121 16.505 1.00 21.77 C ATOM 71 C MET A 93 −23.78532.591 14.932 1.00 31.52 C ATOM 72 O MET A 93 −24.416 32.810 15.973 1.0032.72 O ATOM 73 N THR A 94 −24.311 32.686 13.709 1.00 33.84 N ATOM 74 CATHR A 94 −25.754 32.818 13.520 1.00 35.14 C ATOM 75 CB THR A 94 −26.08033.245 12.094 1.00 35.65 C ATOM 76 OG1 THR A 94 −25.554 32.285 11.1731.00 35.99 O ATOM 77 CG2 THR A 94 −25.481 34.615 11.807 1.00 36.80 CATOM 78 C THR A 94 −26.448 31.512 13.841 1.00 35.97 C ATOM 79 O THR A 94−25.818 30.446 13.913 1.00 34.20 O ATOM 80 N ILE A 95 −27.761 31.58714.029 1.00 36.97 N ATOM 81 CA ILE A 95 −28.575 30.410 14.266 1.00 38.79C ATOM 82 CB ILE A 95 −30.070 30.801 14.496 1.00 38.82 C ATOM 83 CG1 ILEA 95 −30.205 31.659 15.779 1.00 41.36 C ATOM 84 CD1 ILE A 95 −31.70931.841 16.326 1.00 42.00 C ATOM 85 CG2 ILE A 95 −30.911 29.558 14.5981.00 41.63 C ATOM 86 C ILE A 95 −28.396 29.378 13.116 1.00 37.69 C ATOM87 O ILE A 95 −28.268 28.199 13.365 1.00 38.70 O ATOM 88 N GLU A 96−28.378 29.842 11.878 1.00 36.92 N ATOM 89 CA GLU A 96 −28.104 28.99910.700 1.00 36.29 C ATOM 90 CB GLU A 96 −28.239 29.823 9.409 1.00 36.39C ATOM 91 CG GLU A 96 −28.227 29.016 8.087 1.00 38.37 C ATOM 92 CD GLU A96 −26.817 28.589 7.614 1.00 40.56 C ATOM 93 OE1 GLU A 96 −25.874 29.4067.689 1.00 39.66 O ATOM 94 OE2 GLU A 96 −26.666 27.421 7.174 1.00 40.00O ATOM 95 C GLU A 96 −26.709 28.344 10.788 1.00 35.41 C ATOM 96 O GLU A96 −26.605 27.137 10.614 1.00 33.83 O ATOM 97 N GLU A 97 −25.657 29.11411.117 1.00 34.89 N ATOM 98 CA GLU A 97 −24.290 28.538 11.192 1.00 34.19C ATOM 99 CB GLU A 97 −23.215 29.612 11.389 1.00 34.50 C ATOM 100 CG GLUA 97 −22.913 30.437 10.153 1.00 34.90 C ATOM 101 CD GLU A 97 −22.02131.629 10.505 1.00 38.47 C ATOM 102 OE1 GLU A 97 −22.183 32.188 11.6301.00 34.46 O ATOM 103 OE2 GLU A 97 −21.153 31.993 9.675 1.00 39.78 OATOM 104 C GLU A 97 −24.222 27.492 12.285 1.00 34.41 C ATOM 105 O GLU A97 −23.610 26.431 12.128 1.00 33.26 O ATOM 106 N LEU A 98 −24.931 27.75713.379 1.00 33.38 N ATOM 107 CA LEU A 98 −24.975 26.854 14.496 1.0033.56 C ATOM 108 CB LEU A 98 −25.625 27.616 15.676 1.00 35.16 C ATOM 109CG LEU A 98 −25.697 27.103 17.089 1.00 36.28 C ATOM 110 CD1 LEU A 98−24.280 27.030 17.629 1.00 37.99 C ATOM 111 CD2 LEU A 98 −26.556 28.16417.855 1.00 36.53 C ATOM 112 C LEU A 98 −25.721 25.558 14.186 1.00 33.48C ATOM 113 O LEU A 98 −25.383 24.495 14.740 1.00 31.52 O ATOM 114 N SERA 99 −26.735 25.649 13.311 1.00 32.52 N ATOM 115 CA SER A 99 −27.64824.548 13.055 1.00 34.15 C ATOM 116 CB SER A 99 −29.071 25.062 12.7501.00 33.43 C ATOM 117 OG SER A 99 −29.498 25.903 13.802 1.00 40.37 OATOM 118 C SER A 99 −27.246 23.698 11.864 1.00 32.87 C ATOM 119 O SER A99 −27.754 22.584 11.728 1.00 32.22 O ATOM 120 N ARG A 100 −26.34824.228 11.031 1.00 31.55 N ATOM 121 CA ARG A 100 −25.947 23.591 9.7591.00 31.41 C ATOM 122 CB ARG A 100 −24.975 24.509 9.028 1.00 30.90 CATOM 123 CG ARG A 100 −24.884 24.295 7.526 1.00 30.96 C ATOM 124 CD ARGA 100 −23.727 25.099 6.940 1.00 30.21 C ATOM 125 NE ARG A 100 −23.92926.551 7.061 1.00 31.23 N ATOM 126 CZ ARG A 100 −22.966 27.437 6.8861.00 33.84 C ATOM 127 NH1 ARG A 100 −21.733 27.018 6.593 1.00 32.14 NATOM 128 NH2 ARG A 100 −23.220 28.737 7.013 1.00 33.44 N ATOM 129 C ARGA 100 −25.234 22.286 10.023 1.00 30.72 C ATOM 130 O ARG A 100 −24.49522.186 10.990 1.00 31.73 O ATOM 131 N ASP A 101 −25.459 21.277 9.1931.00 30.35 N ATOM 132 CA ASP A 101 −24.662 20.072 9.267 1.00 30.10 CATOM 133 CB ASP A 101 −25.502 18.809 9.060 1.00 30.91 C ATOM 134 CG ASPA 101 −26.681 18.707 10.025 1.00 31.96 C ATOM 135 OD1 ASP A 101 −26.45818.846 11.256 1.00 33.73 O ATOM 136 OD2 ASP A 101 −27.815 18.479 9.5381.00 31.46 O ATOM 137 C ASP A 101 −23.617 20.188 8.171 1.00 29.73 C ATOM138 O ASP A 101 −23.823 20.894 7.189 1.00 30.58 O ATOM 139 N TRP A 102−22.472 19.540 8.345 1.00 29.30 N ATOM 140 CA TRP A 102 −21.402 19.6627.352 1.00 26.90 C ATOM 141 CB TRP A 102 −20.371 20.709 7.759 1.00 27.28C ATOM 142 CG TRP A 102 −19.709 20.410 9.076 1.00 26.50 C ATOM 143 CD1TRP A 102 −20.266 20.538 10.322 1.00 28.05 C ATOM 144 NE1 TRP A 102−19.366 20.185 11.298 1.00 25.18 N ATOM 145 CE2 TRP A 102 −18.179 19.85110.700 1.00 27.63 C ATOM 146 CD2 TRP A 102 −18.363 19.979 9.285 1.0027.61 C ATOM 147 CE3 TRP A 102 −17.290 19.692 8.432 1.00 24.42 C ATOM148 CZ3 TRP A 102 −16.064 19.254 9.001 1.00 24.78 C ATOM 149 CH2 TRP A102 −15.922 19.115 10.407 1.00 27.13 C ATOM 150 CZ2 TRP A 102 −16.97919.406 11.266 1.00 27.85 C ATOM 151 C TRP A 102 −20.799 18.285 7.0861.00 27.67 C ATOM 152 O TRP A 102 −21.014 17.347 7.844 1.00 26.73 O ATOM153 N PHE A 103 −20.040 18.169 5.999 1.00 27.38 N ATOM 154 CA PHE A 103−19.555 16.865 5.544 1.00 26.65 C ATOM 155 CB PHE A 103 −20.066 16.6944.095 1.00 27.13 C ATOM 156 CG PHE A 103 −19.353 15.647 3.275 1.00 29.74C ATOM 157 CD1 PHE A 103 −19.838 14.339 3.223 1.00 32.10 C ATOM 158 CE1PHE A 103 −19.198 13.365 2.419 1.00 29.36 C ATOM 159 CZ PHE A 103−18.095 13.730 1.649 1.00 31.44 C ATOM 160 CE2 PHE A 103 −17.614 15.0361.668 1.00 34.30 C ATOM 161 CD2 PHE A 103 −18.245 15.993 2.478 1.0033.21 C ATOM 162 C PHE A 103 −18.031 16.886 5.539 1.00 25.08 C ATOM 163O PHE A 103 −17.427 17.901 5.181 1.00 25.47 O ATOM 164 N MET A 104−17.418 15.781 5.953 1.00 24.11 N ATOM 165 CA MET A 104 −15.946 15.6015.888 1.00 24.78 C ATOM 166 CB MET A 104 −15.339 15.135 7.242 1.00 23.15C ATOM 167 CG MET A 104 −15.578 16.116 8.425 1.00 25.55 C ATOM 168 SDMET A 104 −15.331 15.278 10.011 1.00 27.07 S ATOM 169 CE MET A 104−16.966 14.670 10.253 1.00 27.39 C ATOM 170 C MET A 104 −15.672 14.5324.832 1.00 24.85 C ATOM 171 O MET A 104 −16.247 13.450 4.874 1.00 25.29O ATOM 172 N LEU A 105 −14.780 14.842 3.893 1.00 25.30 N ATOM 173 CA LEUA 105 −14.315 13.870 2.911 1.00 24.88 C ATOM 174 CB LEU A 105 −13.57714.626 1.795 1.00 24.53 C ATOM 175 CG LEU A 105 −13.109 13.799 0.5931.00 30.23 C ATOM 176 CD1 LEU A 105 −14.315 13.128 −0.104 1.00 27.68 CATOM 177 CD2 LEU A 105 −12.328 14.697 −0.333 1.00 31.62 C ATOM 178 C LEUA 105 −13.473 12.817 3.534 1.00 24.44 C ATOM 179 O LEU A 105 −13.60011.624 3.187 1.00 25.09 O ATOM 180 N MET A 106 −12.600 13.229 4.472 1.0023.86 N ATOM 181 CA MET A 106 −11.733 12.325 5.187 1.00 23.48 C ATOM 182CB MET A 106 −10.253 12.672 4.853 1.00 23.02 C ATOM 183 CG MET A 106−9.897 12.294 3.344 1.00 25.01 C ATOM 184 SD MET A 106 −8.226 12.7802.955 1.00 24.98 S ATOM 185 CE MET A 106 −8.504 13.050 1.171 1.00 33.15C ATOM 186 C MET A 106 −11.987 12.547 6.702 1.00 24.02 C ATOM 187 O META 106 −11.212 13.271 7.351 1.00 22.17 O ATOM 188 N PRO A 107 −13.07011.957 7.235 1.00 25.50 N ATOM 189 CA PRO A 107 −13.453 12.363 8.5971.00 25.66 C ATOM 190 CB PRO A 107 −14.813 11.708 8.812 1.00 26.36 CATOM 191 CG PRO A 107 −15.014 10.716 7.645 1.00 27.67 C ATOM 192 CD PROA 107 −13.963 10.924 6.649 1.00 26.26 C ATOM 193 C PRO A 107 −12.45611.954 9.666 1.00 26.62 C ATOM 194 O PRO A 107 −11.874 10.860 9.627 1.0025.19 O ATOM 195 N LYS A 108 −12.231 12.859 10.610 1.00 27.63 N ATOM 196CA LYS A 108 −11.452 12.532 11.791 1.00 26.56 C ATOM 197 CB LYS A 108−10.124 13.291 11.818 1.00 27.79 C ATOM 198 CG LYS A 108 −9.108 13.04710.659 1.00 28.05 C ATOM 199 CD LYS A 108 −8.192 11.916 10.934 1.0031.20 C ATOM 200 CE LYS A 108 −8.719 10.611 10.548 1.00 30.45 C ATOM 201NZ LYS A 108 −8.945 10.441 9.045 1.00 33.91 N ATOM 202 C LYS A 108−12.304 13.026 12.953 1.00 27.72 C ATOM 203 O LYS A 108 −12.825 14.17712.935 1.00 24.97 O ATOM 204 N GLN A 109 −12.403 12.194 13.977 1.0027.58 N ATOM 205 CA GLN A 109 −13.182 12.573 15.157 1.00 30.64 C ATOM206 CB GLN A 109 −14.621 12.111 15.006 1.00 29.87 C ATOM 207 CG GLN A109 −15.459 12.288 16.241 1.00 39.27 C ATOM 208 CD GLN A 109 −16.68311.376 16.235 1.00 46.13 C ATOM 209 OE1 GLN A 109 −16.724 10.376 16.9701.00 48.01 O ATOM 210 NE2 GLN A 109 −17.666 11.693 15.375 1.00 46.81 NATOM 211 C GLN A 109 −12.504 11.988 16.372 1.00 30.84 C ATOM 212 O GLN A109 −12.006 10.853 16.332 1.00 31.32 O ATOM 213 N LYS A 110 −12.37212.810 17.404 1.00 30.66 N ATOM 214 CA LYS A 110 −11.746 12.430 18.6621.00 33.30 C ATOM 215 CB LYS A 110 −10.384 13.105 18.838 1.00 32.59 CATOM 216 CG LYS A 110 −9.599 12.479 19.944 1.00 39.86 C ATOM 217 CD LYSA 110 −8.308 13.201 20.198 1.00 44.72 C ATOM 218 CE LYS A 110 −7.42412.330 21.064 1.00 49.17 C ATOM 219 NZ LYS A 110 −5.981 12.798 21.0281.00 51.75 N ATOM 220 C LYS A 110 −12.641 12.944 19.806 1.00 33.85 CATOM 221 O LYS A 110 −13.014 14.135 19.846 1.00 32.23 O ATOM 222 N VAL A111 −12.953 12.046 20.738 1.00 34.29 N ATOM 223 CA VAL A 111 −13.60112.447 21.969 1.00 35.38 C ATOM 224 CB VAL A 111 −14.656 11.399 22.4051.00 35.08 C ATOM 225 CG1 VAL A 111 −15.253 11.774 23.720 1.00 36.51 CATOM 226 CG2 VAL A 111 −15.780 11.326 21.306 1.00 34.54 C ATOM 227 C VALA 111 −12.464 12.658 22.927 1.00 36.40 C ATOM 228 O VAL A 111 −11.67711.747 23.143 1.00 37.57 O ATOM 229 N GLU A 112 −12.287 13.899 23.3871.00 36.90 N ATOM 230 CA GLU A 112 −11.288 14.204 24.400 1.00 38.96 CATOM 231 CB GLU A 112 −10.265 15.217 23.913 1.00 39.19 C ATOM 232 CG GLUA 112 −9.175 14.530 23.156 1.00 46.21 C ATOM 233 CD GLU A 112 −7.91215.349 22.990 1.00 51.55 C ATOM 234 OE1 GLU A 112 −7.283 15.197 21.9281.00 53.26 O ATOM 235 OE2 GLU A 112 −7.547 16.134 23.906 1.00 56.88 OATOM 236 C GLU A 112 −12.007 14.718 25.634 1.00 38.39 C ATOM 237 O GLU A112 −12.469 15.865 25.685 1.00 36.96 O ATOM 238 N GLY A 113 −12.14013.822 26.601 1.00 39.27 N ATOM 239 CA GLY A 113 −12.917 14.119 27.7961.00 38.12 C ATOM 240 C GLY A 113 −14.353 14.437 27.464 1.00 36.64 CATOM 241 O GLY A 113 −15.033 13.655 26.776 1.00 38.16 O ATOM 242 N PRO A114 −14.849 15.576 27.964 1.00 33.88 N ATOM 243 CA PRO A 114 −16.23715.943 27.762 1.00 32.13 C ATOM 244 CB PRO A 114 −16.492 16.931 28.9161.00 32.60 C ATOM 245 CG PRO A 114 −15.165 17.627 29.055 1.00 31.81 CATOM 246 CD PRO A 114 −14.126 16.576 28.781 1.00 34.84 C ATOM 247 C PROA 114 −16.509 16.645 26.405 1.00 29.72 C ATOM 248 O PRO A 114 −17.65717.067 26.146 1.00 28.42 O ATOM 249 N LEU A 115 −15.499 16.717 25.5361.00 28.35 N ATOM 250 CA LEU A 115 −15.700 17.376 24.223 1.00 27.24 CATOM 251 CB LEU A 115 −14.794 18.599 24.129 1.00 27.96 C ATOM 252 CG LEUA 115 −14.946 19.667 25.243 1.00 26.94 C ATOM 253 CD1 LEU A 115 −13.75020.612 25.196 1.00 27.95 C ATOM 254 CD2 LEU A 115 −16.251 20.417 25.0991.00 29.72 C ATOM 255 C LEU A 115 −15.357 16.470 23.033 1.00 27.21 CATOM 256 O LEU A 115 −14.434 15.672 23.116 1.00 27.09 O ATOM 257 N CYS A116 −16.031 16.713 21.914 1.00 27.45 N ATOM 258 CA CYS A 116 −15.78315.992 20.659 1.00 26.39 C ATOM 259 CB CYS A 116 −17.108 15.497 20.0901.00 26.69 C ATOM 260 SG CYS A 116 −16.868 14.551 18.501 1.00 31.80 SATOM 261 C CYS A 116 −15.120 16.929 19.656 1.00 25.74 C ATOM 262 O CYS A116 −15.639 18.029 19.409 1.00 25.83 O ATOM 263 N ILE A 117 −13.96016.523 19.126 1.00 24.09 N ATOM 264 CA ILE A 117 −13.283 17.265 18.0481.00 24.27 C ATOM 265 CB ILE A 117 −11.755 17.349 18.356 1.00 25.27 CATOM 266 CG1 ILE A 117 −11.517 17.862 19.806 1.00 23.31 C ATOM 267 CD1ILE A 117 −10.154 17.452 20.379 1.00 26.08 C ATOM 268 CG2 ILE A 117−11.015 18.197 17.315 1.00 22.67 C ATOM 269 C ILE A 117 −13.472 16.57316.692 1.00 23.94 C ATOM 270 O ILE A 117 −13.241 15.340 16.562 1.0023.40 O ATOM 271 N ARG A 118 −13.839 17.358 15.693 1.00 22.86 N ATOM 272CA ARG A 118 −13.972 16.851 14.336 1.00 23.41 C ATOM 273 CB ARG A 118−15.425 16.931 13.889 1.00 24.33 C ATOM 274 CG ARG A 118 −16.195 15.76014.310 1.00 26.67 C ATOM 275 CD ARG A 118 −17.648 16.145 14.171 1.0036.06 C ATOM 276 NE ARG A 118 −18.440 15.040 14.612 1.00 41.48 N ATOM277 CZ ARG A 118 −19.612 15.131 15.215 1.00 45.56 C ATOM 278 NH1 ARG A118 −20.146 16.313 15.465 1.00 46.68 N ATOM 279 NH2 ARG A 118 −20.22814.012 15.596 1.00 45.78 N ATOM 280 C ARG A 118 −13.198 17.713 13.3791.00 23.69 C ATOM 281 O ARG A 118 −13.212 18.954 13.476 1.00 22.65 OATOM 282 N ILE A 119 −12.562 17.060 12.409 1.00 23.73 N ATOM 283 CA ILEA 119 −11.831 17.816 11.420 1.00 24.09 C ATOM 284 CB ILE A 119 −10.41218.129 11.928 1.00 24.22 C ATOM 285 CG1 ILE A 119 −9.636 18.940 10.8821.00 26.11 C ATOM 286 CD1 ILE A 119 −8.270 19.415 11.340 1.00 27.40 CATOM 287 CG2 ILE A 119 −9.677 16.828 12.269 1.00 26.48 C ATOM 288 C ILEA 119 −11.827 17.045 10.087 1.00 23.09 C ATOM 289 O ILE A 119 −11.82315.831 10.101 1.00 24.06 O ATOM 290 N ASP A 120 −11.950 17.754 8.9671.00 21.94 N ATOM 291 CA ASP A 120 −11.754 17.122 7.654 1.00 21.86 CATOM 292 CB ASP A 120 −12.475 17.904 6.535 1.00 22.15 C ATOM 293 CG ASPA 120 −12.612 17.057 5.250 1.00 23.64 C ATOM 294 OD1 ASP A 120 −11.98315.954 5.179 1.00 24.29 O ATOM 295 OD2 ASP A 120 −13.343 17.458 4.3481.00 23.75 O ATOM 296 C ASP A 120 −10.269 17.079 7.331 1.00 21.18 C ATOM297 O ASP A 120 −9.679 18.112 7.116 1.00 21.54 O ATOM 298 N GLN A 121−9.681 15.887 7.316 1.00 21.00 N ATOM 299 CA GLN A 121 −8.259 15.6886.914 1.00 21.84 C ATOM 300 CB GLN A 121 −7.873 14.225 7.121 1.00 22.28C ATOM 301 CG GLN A 121 −6.428 13.911 6.740 1.00 24.84 C ATOM 302 CD GLNA 121 −5.968 12.511 7.069 1.00 25.52 C ATOM 303 OE1 GLN A 121 −6.75411.585 7.276 1.00 23.53 O ATOM 304 NE2 GLN A 121 −4.627 12.340 7.0961.00 25.16 N ATOM 305 C GLN A 121 −7.981 16.150 5.467 1.00 22.62 C ATOM306 O GLN A 121 −6.829 16.437 5.080 1.00 21.93 O ATOM 307 N ALA A 122−9.054 16.261 4.685 1.00 21.71 N ATOM 308 CA ALA A 122 −8.912 16.6173.256 1.00 21.69 C ATOM 309 CB ALA A 122 −10.181 16.141 2.494 1.00 19.71C ATOM 310 C ALA A 122 −8.662 18.107 3.052 1.00 22.50 C ATOM 311 O ALA A122 −8.187 18.546 1.985 1.00 23.74 O ATOM 312 N ILE A 123 −8.969 18.9244.058 1.00 22.64 N ATOM 313 CA ILE A 123 −8.908 20.394 3.883 1.00 22.96C ATOM 314 CB ILE A 123 −9.911 21.109 4.803 1.00 23.42 C ATOM 315 CG1ILE A 123 −11.364 20.728 4.413 1.00 24.78 C ATOM 316 CD1 ILE A 123−11.800 21.234 3.011 1.00 28.40 C ATOM 317 CG2 ILE A 123 −9.756 22.6344.681 1.00 22.20 C ATOM 318 C ILE A 123 −7.508 20.981 4.108 1.00 25.70 CATOM 319 O ILE A 123 −6.947 20.792 5.178 1.00 25.29 O ATOM 320 N MET A124 −6.943 21.662 3.092 1.00 25.17 N ATOM 321 CA MET A 124 −5.579 22.1833.163 1.00 28.51 C ATOM 322 CB MET A 124 −4.655 21.297 2.337 1.00 27.78C ATOM 323 CG MET A 124 −4.771 19.813 2.656 1.00 30.26 C ATOM 324 SD META 124 −3.484 18.782 1.811 1.00 33.51 S ATOM 325 CE MET A 124 −2.05919.361 2.723 1.00 37.42 C ATOM 326 C MET A 124 −5.578 23.562 2.553 1.0028.55 C ATOM 327 O MET A 124 −6.493 23.905 1.787 1.00 27.92 O ATOM 328 NASP A 125 −4.559 24.344 2.895 1.00 29.74 N ATOM 329 CA ASP A 125 −4.21525.614 2.253 1.00 32.07 C ATOM 330 CB ASP A 125 −3.799 25.405 0.762 1.0033.16 C ATOM 331 CG ASP A 125 −2.736 24.338 0.604 1.00 35.13 C ATOM 332OD1 ASP A 125 −1.696 24.451 1.278 1.00 36.19 O ATOM 333 OD2 ASP A 125−2.941 23.385 −0.186 1.00 41.35 O ATOM 334 C ASP A 125 −5.240 26.7192.323 1.00 32.12 C ATOM 335 O ASP A 125 −5.180 27.626 1.509 1.00 33.38 OATOM 336 N LYS A 126 −6.148 26.691 3.299 1.00 31.07 N ATOM 337 CA LYS A126 −7.178 27.720 3.386 1.00 30.62 C ATOM 338 CB LYS A 126 −8.564 27.0493.449 1.00 32.29 C ATOM 339 CG LYS A 126 −8.996 26.577 2.028 1.00 35.51C ATOM 340 CD LYS A 126 −10.152 25.660 2.060 1.00 43.65 C ATOM 341 CELYS A 126 −10.660 25.433 0.631 1.00 44.47 C ATOM 342 NZ LYS A 126−11.170 26.689 −0.085 1.00 46.44 N ATOM 343 C LYS A 126 −6.952 28.7134.534 1.00 29.60 C ATOM 344 O LYS A 126 −6.222 28.422 5.467 1.00 30.24 OATOM 345 N ASN A 127 −7.527 29.897 4.438 1.00 29.11 N ATOM 346 CA ASN A127 −7.523 30.805 5.578 1.00 29.06 C ATOM 347 CB ASN A 127 −7.591 32.2435.112 1.00 29.91 C ATOM 348 CG ASN A 127 −6.308 32.677 4.437 1.00 33.89C ATOM 349 OD1 ASN A 127 −5.214 32.543 4.998 1.00 36.73 O ATOM 350 ND2ASN A 127 −6.427 33.183 3.229 1.00 37.36 N ATOM 351 C ASN A 127 −8.78930.387 6.358 1.00 28.50 C ATOM 352 O ASN A 127 −9.860 30.326 5.787 1.0026.56 O ATOM 353 N ILE A 128 −8.625 30.078 7.639 1.00 27.29 N ATOM 354CA ILE A 128 −9.706 29.462 8.437 1.00 27.38 C ATOM 355 CB ILE A 128−9.295 28.032 8.952 1.00 27.42 C ATOM 356 CG1 ILE A 128 −9.024 27.0377.799 1.00 27.03 C ATOM 357 CD1 ILE A 128 −10.184 26.824 6.863 1.0028.44 C ATOM 358 CG2 ILE A 128 −10.342 27.441 9.962 1.00 26.81 C ATOM359 C ILE A 128 −9.957 30.371 9.641 1.00 27.01 C ATOM 360 O ILE A 128−9.014 30.865 10.239 1.00 27.70 O ATOM 361 N MET A 129 −11.206 30.56610.031 1.00 27.13 N ATOM 362 CA MET A 129 −11.476 31.400 11.217 1.0027.30 C ATOM 363 CB MET A 129 −12.306 32.631 10.834 1.00 27.31 C ATOM364 CG MET A 129 −12.890 33.479 12.058 1.00 28.79 C ATOM 365 SD MET A129 −11.620 34.344 12.939 1.00 32.60 S ATOM 366 CE MET A 129 −11.41035.688 11.799 1.00 39.01 C ATOM 367 C MET A 129 −12.264 30.526 12.1831.00 26.82 C ATOM 368 O MET A 129 −13.285 29.938 11.788 1.00 27.01 OATOM 369 N LEU A 130 −11.813 30.470 13.432 1.00 26.13 N ATOM 370 CA LEUA 130 −12.575 29.765 14.497 1.00 26.12 C ATOM 371 CB LEU A 130 −11.61829.297 15.610 1.00 24.84 C ATOM 372 CG LEU A 130 −10.485 28.337 15.2431.00 27.14 C ATOM 373 CD1 LEU A 130 −10.087 27.626 16.479 1.00 22.57 CATOM 374 CD2 LEU A 130 −10.891 27.282 14.117 1.00 22.23 C ATOM 375 C LEUA 130 −13.601 30.733 15.080 1.00 25.81 C ATOM 376 O LEU A 130 −13.23131.837 15.498 1.00 26.04 O ATOM 377 N LYS A 131 −14.873 30.330 15.0761.00 26.76 N ATOM 378 CA LYS A 131 −15.956 31.068 15.722 1.00 26.56 CATOM 379 CB LYS A 131 −17.004 31.490 14.684 1.00 27.61 C ATOM 380 CG LYSA 131 −16.533 32.568 13.680 1.00 28.89 C ATOM 381 CD LYS A 131 −17.69132.884 12.680 1.00 28.82 C ATOM 382 CE LYS A 131 −17.415 34.227 12.0311.00 38.35 C ATOM 383 NZ LYS A 131 −18.327 34.532 10.898 1.00 41.90 NATOM 384 C LYS A 131 −16.645 30.157 16.768 1.00 26.72 C ATOM 385 O LYS A131 −16.730 28.927 16.598 1.00 24.29 O ATOM 386 N ALA A 132 −17.18830.754 17.832 1.00 24.37 N ATOM 387 CA ALA A 132 −17.802 29.955 18.8811.00 23.81 C ATOM 388 CB ALA A 132 −16.725 29.487 19.941 1.00 23.01 CATOM 389 C ALA A 132 −18.968 30.664 19.540 1.00 24.34 C ATOM 390 O ALA A132 −19.104 31.907 19.494 1.00 24.27 O ATOM 391 N ASN A 133 −19.84529.844 20.107 1.00 24.68 N ATOM 392 CA ASN A 133 −20.919 30.315 20.9811.00 24.43 C ATOM 393 CB ASN A 133 −22.314 29.912 20.475 1.00 23.91 CATOM 394 CG ASN A 133 −22.739 30.645 19.185 1.00 27.90 C ATOM 395 OD1ASN A 133 −21.937 31.202 18.437 1.00 29.10 O ATOM 396 ND2 ASN A 133−24.037 30.641 18.941 1.00 29.92 N ATOM 397 C ASN A 133 −20.631 29.66622.321 1.00 23.54 C ATOM 398 O ASN A 133 −20.369 28.458 22.420 1.0021.57 O ATOM 399 N PHE A 134 −20.630 30.478 23.364 1.00 23.58 N ATOM 400CA PHE A 134 −20.216 30.016 24.672 1.00 23.28 C ATOM 401 CB PHE A 134−18.686 29.889 24.725 1.00 23.19 C ATOM 402 CG PHE A 134 −17.902 31.13824.314 1.00 24.74 C ATOM 403 CD1 PHE A 134 −17.415 32.026 25.291 1.0024.85 C ATOM 404 CE1 PHE A 134 −16.650 33.169 24.927 1.00 26.78 C ATOM405 CZ PHE A 134 −16.343 33.397 23.561 1.00 24.67 C ATOM 406 CE2 PHE A134 −16.823 32.475 22.585 1.00 25.59 C ATOM 407 CD2 PHE A 134 −17.60331.398 22.973 1.00 22.93 C ATOM 408 C PHE A 134 −20.692 30.994 25.7231.00 25.08 C ATOM 409 O PHE A 134 −20.852 32.198 25.446 1.00 24.04 OATOM 410 N SER A 135 −20.907 30.505 26.947 1.00 27.07 N ATOM 411 CA SERA 135 −21.114 31.469 28.052 1.00 27.47 C ATOM 412 CB SER A 135 −22.05230.866 29.115 1.00 28.10 C ATOM 413 OG SER A 135 −21.485 29.691 29.6251.00 27.20 O ATOM 414 C SER A 135 −19.779 31.893 28.672 1.00 28.03 CATOM 415 O SER A 135 −18.787 31.176 28.560 1.00 27.68 O ATOM 416 N VAL A136 −19.759 33.076 29.322 1.00 27.28 N ATOM 417 CA VAL A 136 −18.59833.610 29.998 1.00 27.41 C ATOM 418 CB VAL A 136 −18.080 34.893 29.3011.00 27.85 C ATOM 419 CG1 VAL A 136 −17.743 34.601 27.826 1.00 26.37 CATOM 420 CG2 VAL A 136 −19.146 35.948 29.291 1.00 28.25 C ATOM 421 C VALA 136 −18.984 33.932 31.476 1.00 27.55 C ATOM 422 O VAL A 136 −20.12734.219 31.766 1.00 28.10 O ATOM 423 N ILE A 137 −18.023 33.867 32.3651.00 28.59 N ATOM 424 CA ILE A 137 −18.216 34.244 33.773 1.00 30.78 CATOM 425 CB ILE A 137 −18.669 32.988 34.633 1.00 31.59 C ATOM 426 CG1ILE A 137 −19.278 33.429 35.970 1.00 33.63 C ATOM 427 CD1 ILE A 137−19.700 32.180 36.817 1.00 33.97 C ATOM 428 CG2 ILE A 137 −17.505 31.98734.863 1.00 30.94 C ATOM 429 C ILE A 137 −16.849 34.653 34.155 1.0029.64 C ATOM 430 O ILE A 137 −15.907 34.068 33.633 1.00 29.94 O ATOM 431N PHE A 138 −16.694 35.682 35.016 1.00 29.62 N ATOM 432 CA PHE A 138−15.376 36.106 35.473 1.00 27.79 C ATOM 433 CB PHE A 138 −14.703 35.10136.440 1.00 28.87 C ATOM 434 CG PHE A 138 −15.633 34.568 37.491 1.0031.41 C ATOM 435 CD1 PHE A 138 −15.510 33.255 37.960 1.00 33.05 C ATOM436 CE1 PHE A 138 −16.400 32.772 38.924 1.00 32.87 C ATOM 437 CZ PHE A138 −17.415 33.603 39.441 1.00 32.93 C ATOM 438 CE2 PHE A 138 −17.53534.898 38.987 1.00 32.39 C ATOM 439 CD2 PHE A 138 −16.637 35.374 38.0081.00 31.10 C ATOM 440 C PHE A 138 −14.432 36.427 34.313 1.00 27.04 CATOM 441 O PHE A 138 −13.237 36.182 34.391 1.00 26.40 O ATOM 442 N ASP A139 −14.950 37.048 33.271 1.00 27.25 N ATOM 443 CA ASP A 139 −14.05937.476 32.165 1.00 28.11 C ATOM 444 CB ASP A 139 −12.995 38.467 32.6861.00 26.07 C ATOM 445 CG ASP A 139 −12.315 39.241 31.545 1.00 24.48 CATOM 446 OD1 ASP A 139 −13.054 39.624 30.621 1.00 23.66 O ATOM 447 OD2ASP A 139 −11.077 39.441 31.582 0.50 20.56 O ATOM 448 C ASP A 139−13.343 36.319 31.435 1.00 28.35 C ATOM 449 O ASP A 139 −12.247 36.50030.876 1.00 29.04 O ATOM 450 N ARG A 140 −13.949 35.142 31.450 1.0028.71 N ATOM 451 CA ARG A 140 −13.370 33.986 30.757 1.00 30.54 C ATOM452 CB ARG A 140 −12.409 33.226 31.674 1.00 31.65 C ATOM 453 CG ARG A140 −13.182 32.536 32.786 1.00 35.69 C ATOM 454 CD ARG A 140 −12.36331.446 33.453 1.00 41.63 C ATOM 455 NE ARG A 140 −12.991 31.094 34.7221.00 45.91 N ATOM 456 CZ ARG A 140 −13.998 30.238 34.861 1.00 49.56 CATOM 457 NH1 ARG A 140 −14.524 29.612 33.793 1.00 48.61 N ATOM 458 NH2ARG A 140 −14.475 30.001 36.082 1.00 49.00 N ATOM 459 C ARG A 140−14.482 33.073 30.279 1.00 29.51 C ATOM 460 O ARG A 140 −15.596 33.10330.785 1.00 30.10 O ATOM 461 N LEU A 141 −14.182 32.268 29.264 1.0030.56 N ATOM 462 CA LEU A 141 −15.155 31.290 28.753 1.00 29.62 C ATOM463 CB LEU A 141 −14.496 30.410 27.659 1.00 29.02 C ATOM 464 CG LEU A141 −15.359 29.328 27.005 1.00 30.21 C ATOM 465 CD1 LEU A 141 −14.99829.213 25.514 1.00 25.61 C ATOM 466 CD2 LEU A 141 −15.146 27.989 27.6891.00 28.22 C ATOM 467 C LEU A 141 −15.579 30.396 29.907 1.00 29.31 CATOM 468 O LEU A 141 −14.754 29.975 30.687 1.00 29.67 O ATOM 469 N GLU A142 −16.862 30.108 29.994 1.00 28.07 N ATOM 470 CA GLU A 142 −17.35229.241 31.047 1.00 28.71 C ATOM 471 CB GLU A 142 −18.590 29.848 31.6671.00 29.55 C ATOM 472 CG GLU A 142 −19.167 28.964 32.766 1.00 32.35 CATOM 473 CD GLU A 142 −20.382 29.575 33.338 1.00 38.85 C ATOM 474 OE1GLU A 142 −20.438 29.665 34.586 1.00 43.19 O ATOM 475 OE2 GLU A 142−21.250 30.017 32.550 1.00 42.00 O ATOM 476 C GLU A 142 −17.759 27.88830.468 1.00 27.92 C ATOM 477 O GLU A 142 −17.164 26.875 30.802 1.0028.27 O ATOM 478 N THR A 143 −18.763 27.910 29.593 1.00 27.95 N ATOM 479CA THR A 143 −19.305 26.688 28.986 1.00 28.53 C ATOM 480 CB THR A 143−20.710 26.388 29.572 1.00 28.46 C ATOM 481 OG1 THR A 143 −20.565 26.17730.990 1.00 30.36 O ATOM 482 CG2 THR A 143 −21.331 25.138 28.946 1.0032.14 C ATOM 483 C THR A 143 −19.370 26.837 27.462 1.00 27.05 C ATOM 484O THR A 143 −20.027 27.702 26.949 1.00 28.79 O ATOM 485 N LEU A 144−18.719 25.950 26.736 1.00 26.74 N ATOM 486 CA LEU A 144 −18.790 25.98825.263 1.00 23.71 C ATOM 487 CB LEU A 144 −17.608 25.189 24.712 1.0023.74 C ATOM 488 CG LEU A 144 −17.563 25.142 23.164 1.00 23.31 C ATOM489 CD1 LEU A 144 −17.213 26.514 22.590 1.00 23.32 C ATOM 490 CD2 LEU A144 −16.567 24.119 22.730 1.00 22.22 C ATOM 491 C LEU A 144 −20.11925.426 24.797 1.00 24.71 C ATOM 492 O LEU A 144 −20.529 24.338 25.2421.00 24.35 O ATOM 493 N ILE A 145 −20.821 26.133 23.923 1.00 23.45 NATOM 494 CA ILE A 145 −21.970 25.538 23.265 1.00 25.19 C ATOM 495 CB ILEA 145 −23.055 26.592 23.018 1.00 25.84 C ATOM 496 CG1 ILE A 145 −23.64027.052 24.388 1.00 30.13 C ATOM 497 CD1 ILE A 145 −24.255 28.496 24.2721.00 38.82 C ATOM 498 CG2 ILE A 145 −24.150 26.089 22.057 1.00 26.97 CATOM 499 C ILE A 145 −21.515 24.854 21.938 1.00 25.87 C ATOM 500 O ILE A145 −21.817 23.679 21.687 1.00 23.59 O ATOM 501 N LEU A 146 −20.77225.593 21.112 1.00 25.26 N ATOM 502 CA LEU A 146 −20.211 24.985 19.8931.00 23.95 C ATOM 503 CB LEU A 146 −21.302 24.942 18.833 1.00 23.73 CATOM 504 CG LEU A 146 −21.016 24.183 17.505 1.00 24.90 C ATOM 505 CD1LEU A 146 −20.763 22.691 17.791 1.00 25.12 C ATOM 506 CD2 LEU A 146−22.185 24.339 16.580 1.00 24.67 C ATOM 507 C LEU A 146 −19.118 25.87419.383 1.00 23.11 C ATOM 508 O LEU A 146 −19.292 27.130 19.424 1.0022.17 O ATOM 509 N LEU A 147 −18.034 25.281 18.835 1.00 22.70 N ATOM 510CA LEU A 147 −17.008 26.058 18.122 1.00 21.78 C ATOM 511 CB LEU A 147−15.647 25.947 18.857 1.00 22.68 C ATOM 512 CG LEU A 147 −14.450 26.65318.206 1.00 22.20 C ATOM 513 CD1 LEU A 147 −13.385 27.062 19.271 1.0020.77 C ATOM 514 CD2 LEU A 147 −13.814 25.775 17.088 1.00 19.37 C ATOM515 C LEU A 147 −16.907 25.455 16.717 1.00 22.57 C ATOM 516 O LEU A 147−16.910 24.212 16.593 1.00 20.70 O ATOM 517 N ARG A 148 −16.848 26.29315.663 1.00 22.59 N ATOM 518 CA ARG A 148 −16.671 25.730 14.283 1.0023.35 C ATOM 519 CB ARG A 148 −17.969 25.749 13.455 1.00 22.58 C ATOM520 CG ARG A 148 −18.861 24.593 13.818 1.00 23.66 C ATOM 521 CD ARG A148 −20.240 24.671 13.269 1.00 23.87 C ATOM 522 NE ARG A 148 −20.80423.336 13.367 1.00 23.59 N ATOM 523 CZ ARG A 148 −22.035 22.980 12.9781.00 25.11 C ATOM 524 NH1 ARG A 148 −22.902 23.870 12.516 1.00 22.41 NATOM 525 NH2 ARG A 148 −22.395 21.722 13.079 1.00 22.69 N ATOM 526 C ARGA 148 −15.582 26.490 13.594 1.00 23.50 C ATOM 527 O ARG A 148 −15.32927.665 13.935 1.00 23.78 O ATOM 528 N ALA A 149 −14.904 25.785 12.6961.00 23.63 N ATOM 529 CA ALA A 149 −13.834 26.339 11.887 1.00 22.68 CATOM 530 CB ALA A 149 −12.672 25.334 11.840 1.00 21.04 C ATOM 531 C ALAA 149 −14.403 26.626 10.477 1.00 23.39 C ATOM 532 O ALA A 149 −14.90425.710 9.830 1.00 22.23 O ATOM 533 N PHE A 150 −14.330 27.903 10.0331.00 23.42 N ATOM 534 CA PHE A 150 −14.947 28.333 8.761 1.00 24.77 CATOM 535 CB PHE A 150 −15.867 29.532 9.015 1.00 24.60 C ATOM 536 CG PHEA 150 −17.135 29.184 9.792 1.00 26.17 C ATOM 537 CD1 PHE A 150 −17.13329.193 11.188 1.00 25.87 C ATOM 538 CE1 PHE A 150 −18.268 28.861 11.9191.00 27.48 C ATOM 539 CZ PHE A 150 −19.440 28.542 11.266 1.00 25.00 CATOM 540 CE2 PHE A 150 −19.474 28.526 9.862 1.00 26.61 C ATOM 541 CD2PHE A 150 −18.288 28.825 9.124 1.00 25.13 C ATOM 542 C PHE A 150 −13.89528.796 7.717 1.00 24.98 C ATOM 543 O PHE A 150 −12.963 29.457 8.072 1.0024.09 O ATOM 544 N THR A 151 −14.067 28.444 6.438 1.00 27.78 N ATOM 545CA THR A 151 −13.220 28.983 5.382 1.00 29.28 C ATOM 546 CB THR A 151−13.312 28.158 4.077 1.00 28.87 C ATOM 547 OG1 THR A 151 −14.613 28.3023.542 1.00 29.93 O ATOM 548 CG2 THR A 151 −13.106 26.674 4.323 1.0029.18 C ATOM 549 C THR A 151 −13.743 30.414 5.115 1.00 31.10 C ATOM 550O THR A 151 −14.779 30.810 5.628 1.00 29.33 O ATOM 551 N GLU A 152−13.033 31.168 4.282 1.00 33.68 N ATOM 552 CA GLU A 152 −13.425 32.5303.902 1.00 36.84 C ATOM 553 CB GLU A 152 −12.347 33.131 2.999 1.00 37.30C ATOM 554 CG GLU A 152 −11.005 33.248 3.642 1.00 39.17 C ATOM 555 CDGLU A 152 −10.026 34.031 2.777 1.00 48.59 C ATOM 556 OE1 GLU A 152−9.561 33.489 1.748 1.00 51.49 O ATOM 557 OE2 GLU A 152 −9.735 35.1913.123 1.00 49.86 O ATOM 558 C GLU A 152 −14.765 32.567 3.170 1.00 37.80C ATOM 559 O GLU A 152 −15.468 33.595 3.173 1.00 39.18 O ATOM 560 N GLUA 153 −15.098 31.444 2.547 1.00 38.19 N ATOM 561 CA GLU A 153 −16.33731.296 1.834 1.00 39.91 C ATOM 562 CB GLU A 153 −16.145 30.349 0.6331.00 41.25 C ATOM 563 CG GLU A 153 −15.204 30.939 −0.498 1.00 47.72 CATOM 564 CD GLU A 153 −15.857 32.067 −1.366 1.00 56.46 C ATOM 565 OE1GLU A 153 −17.009 32.489 −1.073 1.00 59.59 O ATOM 566 OE2 GLU A 153−15.213 32.532 −2.361 1.00 59.71 O ATOM 567 C GLU A 153 −17.466 30.8252.747 1.00 39.18 C ATOM 568 O GLU A 153 −18.595 30.594 2.283 1.00 40.28O ATOM 569 N GLY A 154 −17.183 30.645 4.037 1.00 36.32 N ATOM 570 CA GLYA 154 −18.270 30.319 4.947 1.00 33.51 C ATOM 571 C GLY A 154 −18.50628.837 5.178 1.00 31.90 C ATOM 572 O GLY A 154 −19.430 28.472 5.925 1.0031.26 O ATOM 573 N ALA A 155 −17.682 27.983 4.576 1.00 29.65 N ATOM 574CA ALA A 155 −17.837 26.524 4.714 1.00 28.90 C ATOM 575 CB ALA A 155−17.137 25.812 3.566 1.00 28.42 C ATOM 576 C ALA A 155 −17.242 26.0216.058 1.00 27.62 C ATOM 577 O ALA A 155 −16.182 26.465 6.447 1.00 27.58O ATOM 578 N ILE A 156 −17.872 25.034 6.677 1.00 26.27 N ATOM 579 CA ILEA 156 −17.329 24.438 7.943 1.00 25.83 C ATOM 580 CB ILE A 156 −18.49523.902 8.878 1.00 24.89 C ATOM 581 CG1 ILE A 156 −19.502 25.006 9.1431.00 25.36 C ATOM 582 CD1 ILE A 156 −20.917 24.545 9.521 1.00 25.07 CATOM 583 CG2 ILE A 156 −17.916 23.352 10.265 1.00 24.02 C ATOM 584 C ILEA 156 −16.376 23.290 7.644 1.00 25.13 C ATOM 585 O ILE A 156 −16.73722.408 6.867 1.00 25.16 O ATOM 586 N VAL A 157 −15.170 23.316 8.241 1.0024.13 N ATOM 587 CA VAL A 157 −14.131 22.283 8.038 1.00 24.32 C ATOM 588CB VAL A 157 −12.963 22.870 7.253 1.00 24.35 C ATOM 589 CG1 VAL A 157−13.491 23.401 5.896 1.00 24.56 C ATOM 590 CG2 VAL A 157 −12.253 24.0098.052 1.00 23.30 C ATOM 591 C VAL A 157 −13.643 21.653 9.369 1.00 24.38C ATOM 592 O VAL A 157 −12.742 20.787 9.381 1.00 24.39 O ATOM 593 N GLYA 158 −14.280 22.055 10.480 1.00 22.71 N ATOM 594 CA GLY A 158 −13.81721.558 11.800 1.00 22.42 C ATOM 595 C GLY A 158 −14.768 22.001 12.8691.00 22.76 C ATOM 596 O GLY A 158 −15.476 22.988 12.689 1.00 22.09 OATOM 597 N GLU A 159 −14.778 21.272 13.985 1.00 22.77 N ATOM 598 CA GLUA 159 −15.685 21.643 15.055 1.00 23.62 C ATOM 599 CB GLU A 159 −17.07621.080 14.702 1.00 23.86 C ATOM 600 CG GLU A 159 −18.105 20.927 15.7381.00 27.75 C ATOM 601 CD GLU A 159 −19.298 20.220 15.110 1.00 30.96 CATOM 602 OE1 GLU A 159 −19.649 19.085 15.511 1.00 33.41 O ATOM 603 OE2GLU A 159 −19.793 20.784 14.126 1.00 31.84 O ATOM 604 C GLU A 159−15.224 21.096 16.400 1.00 23.45 C ATOM 605 O GLU A 159 −14.503 20.08316.451 1.00 23.41 O ATOM 606 N ILE A 160 −15.623 21.803 17.461 1.0021.90 N ATOM 607 CA ILE A 160 −15.490 21.267 18.833 1.00 22.61 C ATOM608 CB ILE A 160 −14.472 21.994 19.660 1.00 22.90 C ATOM 609 CG1 ILE A160 −13.072 21.846 19.064 1.00 20.56 C ATOM 610 CD1 ILE A 160 −12.06822.911 19.659 1.00 23.51 C ATOM 611 CG2 ILE A 160 −14.473 21.422 21.1601.00 20.30 C ATOM 612 C ILE A 160 −16.868 21.407 19.432 1.00 23.34 CATOM 613 O ILE A 160 −17.471 22.524 19.438 1.00 21.20 O ATOM 614 N SER A161 −17.418 20.269 19.860 1.00 25.69 N ATOM 615 CA SER A 161 −18.75820.307 20.418 1.00 28.95 C ATOM 616 CB SER A 161 −19.773 19.669 19.4761.00 30.16 C ATOM 617 OG SER A 161 −19.433 18.304 19.310 1.00 36.69 OATOM 618 C SER A 161 −18.770 19.573 21.739 1.00 31.31 C ATOM 619 O SER A161 −18.092 18.550 21.879 1.00 32.13 O ATOM 620 N PRO A 162 −19.56520.074 22.721 1.00 32.42 N ATOM 621 CA PRO A 162 −19.717 19.308 23.9671.00 32.99 C ATOM 622 CB PRO A 162 −20.635 20.208 24.823 1.00 33.01 CATOM 623 CG PRO A 162 −21.460 21.013 23.754 1.00 34.38 C ATOM 624 CD PROA 162 −20.382 21.303 22.712 1.00 31.98 C ATOM 625 C PRO A 162 −20.41617.973 23.669 1.00 34.31 C ATOM 626 O PRO A 162 −21.251 17.896 22.7701.00 33.06 O ATOM 627 N LEU A 163 −20.094 16.942 24.424 1.00 35.01 NATOM 628 CA LEU A 163 −20.872 15.726 24.360 1.00 39.63 C ATOM 629 CB LEUA 163 −20.148 14.628 25.128 1.00 37.49 C ATOM 630 CG LEU A 163 −18.77014.289 24.594 1.00 38.56 C ATOM 631 CD1 LEU A 163 −18.110 13.411 25.5961.00 42.42 C ATOM 632 CD2 LEU A 163 −18.870 13.613 23.197 1.00 37.70 CATOM 633 C LEU A 163 −22.287 15.986 24.964 1.00 43.24 C ATOM 634 O LEU A163 −22.429 16.761 25.922 1.00 42.85 O ATOM 635 N PRO A 164 −23.32915.347 24.407 1.00 47.70 N ATOM 636 CA PRO A 164 −24.713 15.544 24.9041.00 50.86 C ATOM 637 CB PRO A 164 −25.488 14.431 24.216 1.00 50.96 CATOM 638 CG PRO A 164 −24.731 14.153 22.964 1.00 50.70 C ATOM 639 CD PROA 164 −23.272 14.390 23.288 1.00 48.08 C ATOM 640 C PRO A 164 −24.77815.330 26.404 1.00 53.85 C ATOM 641 O PRO A 164 −25.371 16.133 27.1441.00 55.14 O ATOM 642 N SER A 165 −24.109 14.268 26.836 1.00 56.89 NATOM 643 CA SER A 165 −24.161 13.771 28.201 1.00 59.40 C ATOM 644 CB SERA 165 −23.132 12.627 28.372 1.00 59.96 C ATOM 645 OG SER A 165 −22.73611.981 27.151 1.00 61.14 O ATOM 646 C SER A 165 −23.886 14.862 29.2611.00 60.68 C ATOM 647 O SER A 165 −24.578 14.937 30.285 1.00 61.29 OATOM 648 N PHE A 166 −22.862 15.683 29.014 1.00 61.57 N ATOM 649 CA PHEA 166 −22.397 16.669 29.980 1.00 61.86 C ATOM 650 CB PHE A 166 −20.87816.850 29.924 1.00 62.01 C ATOM 651 CG PHE A 166 −20.108 15.569 29.7801.00 62.40 C ATOM 652 CD1 PHE A 166 −19.110 15.241 30.690 1.00 63.33 CATOM 653 CE1 PHE A 166 −18.373 14.035 30.563 1.00 65.13 C ATOM 654 CZPHE A 166 −18.651 13.167 29.514 1.00 64.22 C ATOM 655 CE2 PHE A 166−19.666 13.493 28.597 1.00 64.14 C ATOM 656 CD2 PHE A 166 −20.371 14.69128.729 1.00 62.88 C ATOM 657 C PHE A 166 −23.042 18.021 29.748 1.0062.36 C ATOM 658 O PHE A 166 −23.417 18.368 28.598 1.00 62.89 O ATOM 659N PRO A 167 −23.210 18.775 30.845 1.00 62.06 N ATOM 660 CA PRO A 167−23.394 20.224 30.872 1.00 61.87 C ATOM 661 CB PRO A 167 −24.570 20.37931.857 1.00 61.66 C ATOM 662 CG PRO A 167 −24.317 19.276 32.881 1.0062.79 C ATOM 663 CD PRO A 167 −23.353 18.232 32.208 1.00 62.77 C ATOM664 C PRO A 167 −22.130 20.921 31.431 1.00 60.38 C ATOM 665 O PRO A 167−22.154 22.141 31.695 1.00 61.90 O ATOM 666 N GLY A 168 −21.050 20.14831.606 1.00 57.49 N ATOM 667 CA GLY A 168 −19.868 20.625 32.321 1.0053.21 C ATOM 668 C GLY A 168 −18.504 20.149 31.843 1.00 49.27 C ATOM 669O GLY A 168 −18.198 18.926 31.777 1.00 49.67 O ATOM 670 N HIS A 169−17.681 21.149 31.549 1.00 44.84 N ATOM 671 CA HIS A 169 −16.297 20.97631.148 1.00 40.46 C ATOM 672 CB HIS A 169 −16.170 20.820 29.602 1.0038.65 C ATOM 673 CG HIS A 169 −16.962 21.841 28.822 1.00 33.52 C ATOM674 ND1 HIS A 169 −18.188 21.564 28.261 1.00 31.35 N ATOM 675 CE1 HIS A169 −18.660 22.637 27.660 1.00 28.39 C ATOM 676 NE2 HIS A 169 −17.79623.616 27.828 1.00 28.28 N ATOM 677 CD2 HIS A 169 −16.724 23.149 28.5531.00 30.88 C ATOM 678 C HIS A 169 −15.680 22.280 31.615 1.00 39.31 CATOM 679 O HIS A 169 −16.410 23.196 32.044 1.00 40.25 O ATOM 680 N THR A170 −14.353 22.339 31.567 1.00 36.78 N ATOM 681 CA THR A 170 −13.57223.479 32.029 1.00 35.94 C ATOM 682 CB THR A 170 −12.377 23.065 32.9271.00 35.25 C ATOM 683 OG1 THR A 170 −11.388 22.393 32.139 1.00 34.72 OATOM 684 CG2 THR A 170 −12.827 22.132 34.101 1.00 36.64 C ATOM 685 C THRA 170 −13.000 24.216 30.823 1.00 35.21 C ATOM 686 O THR A 170 −12.94623.678 29.710 1.00 34.35 O ATOM 687 N ILE A 171 −12.568 25.444 31.0581.00 33.91 N ATOM 688 CA ILE A 171 −11.914 26.233 30.027 1.00 33.18 CATOM 689 CB ILE A 171 −11.670 27.696 30.532 1.00 32.72 C ATOM 690 CG1ILE A 171 −11.151 28.586 29.382 1.00 33.82 C ATOM 691 CD1 ILE A 171−11.256 30.068 29.689 1.00 32.91 C ATOM 692 CG2 ILE A 171 −10.725 27.73231.733 1.00 33.57 C ATOM 693 C ILE A 171 −10.620 25.547 29.575 1.0032.14 C ATOM 694 O ILE A 171 −10.221 25.637 28.412 1.00 31.34 O ATOM 695N GLU A 172 −9.965 24.841 30.492 1.00 31.90 N ATOM 696 CA GLU A 172−8.761 24.099 30.150 1.00 32.76 C ATOM 697 CB GLU A 172 −8.014 23.59631.399 1.00 33.50 C ATOM 698 CG GLU A 172 −7.752 24.691 32.487 1.0038.99 C ATOM 699 CD GLU A 172 −8.749 24.570 33.660 1.00 46.04 C ATOM 700OE1 GLU A 172 −8.553 23.659 34.517 1.00 53.70 O ATOM 701 OE2 GLU A 172−9.725 25.351 33.744 1.00 48.14 O ATOM 702 C GLU A 172 −9.055 22.91629.185 1.00 31.70 C ATOM 703 O GLU A 172 −8.256 22.649 28.286 1.00 31.20O ATOM 704 N ASP A 173 −10.171 22.207 29.399 1.00 31.31 N ATOM 705 CAASP A 173 −10.650 21.204 28.408 1.00 30.63 C ATOM 706 CB ASP A 173−12.011 20.603 28.808 1.00 29.29 C ATOM 707 CG ASP A 173 −11.929 19.74530.069 1.00 32.36 C ATOM 708 OD1 ASP A 173 −10.912 19.089 30.317 1.0036.48 O ATOM 709 OD2 ASP A 173 −12.885 19.746 30.820 1.00 29.46 O ATOM710 C ASP A 173 −10.859 21.898 27.049 1.00 29.18 C ATOM 711 O ASP A 173−10.512 21.341 25.994 1.00 28.08 O ATOM 712 N VAL A 174 −11.483 23.07127.081 1.00 27.66 N ATOM 713 CA VAL A 174 −11.768 23.785 25.829 1.0027.50 C ATOM 714 CB VAL A 174 −12.677 25.024 26.047 1.00 28.13 C ATOM715 CG1 VAL A 174 −12.760 25.860 24.766 1.00 27.42 C ATOM 716 CG2 VAL A174 −14.062 24.576 26.464 1.00 26.02 C ATOM 717 C VAL A 174 −10.45924.167 25.150 1.00 28.12 C ATOM 718 O VAL A 174 −10.288 23.952 23.9121.00 26.80 O ATOM 719 N LYS A 175 −9.517 24.720 25.913 1.00 27.32 N ATOM720 CA LYS A 175 −8.229 25.090 25.333 1.00 29.37 C ATOM 721 CB LYS A 175−7.336 25.851 26.319 1.00 29.49 C ATOM 722 CG LYS A 175 −7.873 27.27726.719 1.00 31.65 C ATOM 723 CD LYS A 175 −7.042 27.779 27.947 1.0034.24 C ATOM 724 CE LYS A 175 −6.548 29.216 27.757 1.00 43.77 C ATOM 725NZ LYS A 175 −5.086 29.241 28.061 1.00 49.63 N ATOM 726 C LYS A 175−7.475 23.894 24.764 1.00 29.15 C ATOM 727 O LYS A 175 −6.905 23.98923.676 1.00 29.98 O ATOM 728 N ASN A 176 −7.464 22.772 25.485 1.00 28.78N ATOM 729 CA ASN A 176 −6.806 21.577 24.971 1.00 29.56 C ATOM 730 CBASN A 176 −7.002 20.378 25.906 1.00 29.89 C ATOM 731 CG ASN A 176 −6.19020.483 27.181 1.00 37.18 C ATOM 732 OD1 ASN A 176 −6.501 19.795 28.1751.00 42.17 O ATOM 733 ND2 ASN A 176 −5.141 21.338 27.178 1.00 41.19 NATOM 734 C ASN A 176 −7.387 21.203 23.614 1.00 27.60 C ATOM 735 O ASN A176 −6.648 20.894 22.683 1.00 27.59 O ATOM 736 N ALA A 177 −8.705 21.20223.527 1.00 25.47 N ATOM 737 CA ALA A 177 −9.386 20.816 22.292 1.0025.42 C ATOM 738 CB ALA A 177 −10.899 20.715 22.505 1.00 23.91 C ATOM739 C ALA A 177 −9.070 21.744 21.148 1.00 24.79 C ATOM 740 O ALA A 177−8.944 21.266 20.001 1.00 25.02 O ATOM 741 N ILE A 178 −9.013 23.06021.440 1.00 23.30 N ATOM 742 CA ILE A 178 −8.731 24.063 20.464 1.0024.16 C ATOM 743 CB ILE A 178 −8.883 25.496 21.039 1.00 23.64 C ATOM 744CG1 ILE A 178 −10.344 25.862 21.218 1.00 23.43 C ATOM 745 CD1 ILE A 178−10.566 27.275 21.940 1.00 24.62 C ATOM 746 CG2 ILE A 178 −8.167 26.51820.104 1.00 24.53 C ATOM 747 C ILE A 178 −7.307 23.869 19.924 1.00 25.28C ATOM 748 O ILE A 178 −7.076 23.950 18.708 1.00 23.52 O ATOM 749 N GLYA 179 −6.361 23.568 20.821 1.00 25.82 N ATOM 750 CA GLY A 179 −4.99423.233 20.391 1.00 24.95 C ATOM 751 C GLY A 179 −4.920 22.005 19.4831.00 26.34 C ATOM 752 O GLY A 179 −4.115 21.988 18.537 1.00 25.96 O ATOM753 N VAL A 180 −5.757 20.999 19.713 1.00 25.94 N ATOM 754 CA VAL A 180−5.748 19.794 18.840 1.00 27.50 C ATOM 755 CB VAL A 180 −6.549 18.63219.443 1.00 28.63 C ATOM 756 CG1 VAL A 180 −6.696 17.436 18.427 1.0030.08 C ATOM 757 CG2 VAL A 180 −5.898 18.139 20.725 1.00 29.50 C ATOM758 C VAL A 180 −6.301 20.114 17.428 1.00 27.72 C ATOM 759 O VAL A 180−5.723 19.737 16.403 1.00 27.57 O ATOM 760 N LEU A 181 −7.435 20.81117.415 1.00 26.46 N ATOM 761 CA LEU A 181 −8.043 21.334 16.195 1.0026.40 C ATOM 762 CB LEU A 181 −9.400 22.036 16.521 1.00 25.50 C ATOM 763CG LEU A 181 −10.103 22.583 15.258 1.00 25.35 C ATOM 764 CD1 LEU A 181−10.370 21.411 14.239 1.00 23.23 C ATOM 765 CD2 LEU A 181 −11.377 23.34815.605 1.00 25.48 C ATOM 766 C LEU A 181 −7.092 22.262 15.412 1.00 25.60C ATOM 767 O LEU A 181 −6.849 22.045 14.207 1.00 23.63 O ATOM 768 N ILEA 182 −6.577 23.300 16.058 1.00 24.97 N ATOM 769 CA ILE A 182 −5.65224.214 15.375 1.00 26.01 C ATOM 770 CB ILE A 182 −5.196 25.420 16.2911.00 26.44 C ATOM 771 CG1 ILE A 182 −6.341 26.404 16.468 1.00 26.81 CATOM 772 CD1 ILE A 182 −6.078 27.572 17.483 1.00 25.50 C ATOM 773 CG2ILE A 182 −4.006 26.171 15.657 1.00 26.76 C ATOM 774 C ILE A 182 −4.40123.498 14.849 1.00 27.06 C ATOM 775 O ILE A 182 −3.903 23.798 13.7371.00 27.99 O ATOM 776 N GLY A 183 −3.903 22.544 15.625 1.00 26.95 N ATOM777 CA GLY A 183 −2.733 21.763 15.236 1.00 27.09 C ATOM 778 C GLY A 183−2.939 20.942 13.966 1.00 27.16 C ATOM 779 O GLY A 183 −2.035 20.85213.118 1.00 25.04 O ATOM 780 N GLY A 184 −4.143 20.391 13.798 1.00 26.79N ATOM 781 CA GLY A 184 −4.454 19.527 12.642 1.00 26.69 C ATOM 782 C GLYA 184 −4.633 20.410 11.450 1.00 26.33 C ATOM 783 O GLY A 184 −4.12720.120 10.380 1.00 26.17 O ATOM 784 N LEU A 185 −5.313 21.534 11.6381.00 26.30 N ATOM 785 CA LEU A 185 −5.499 22.492 10.565 1.00 24.55 CATOM 786 CB LEU A 185 −6.415 23.616 11.001 1.00 23.84 C ATOM 787 CG LEUA 185 −7.888 23.220 11.293 1.00 23.68 C ATOM 788 CD1 LEU A 185 −8.59924.422 12.020 1.00 23.04 C ATOM 789 CD2 LEU A 185 −8.559 22.845 9.9591.00 21.51 C ATOM 790 C LEU A 185 −4.175 23.072 10.089 1.00 26.07 C ATOM791 O LEU A 185 −3.967 23.195 8.863 1.00 24.84 O ATOM 792 N GLU A 186−3.320 23.489 11.021 1.00 24.68 N ATOM 793 CA GLU A 186 −1.974 24.02910.643 1.00 26.89 C ATOM 794 CB GLU A 186 −1.271 24.702 11.828 1.0026.28 C ATOM 795 CG GLU A 186 −1.956 25.957 12.224 1.00 29.68 C ATOM 796CD GLU A 186 −1.329 26.627 13.460 1.00 30.75 C ATOM 797 OE1 GLU A 186−0.559 25.977 14.192 1.00 36.73 O ATOM 798 OE2 GLU A 186 −1.625 27.80413.670 1.00 33.71 O ATOM 799 C GLU A 186 −1.046 23.007 10.020 1.00 27.78C ATOM 800 O GLU A 186 −0.236 23.366 9.102 1.00 28.87 O ATOM 801 N TRP A187 −1.120 21.762 10.495 1.00 29.22 N ATOM 802 CA TRP A 187 −0.40220.622 9.874 1.00 30.02 C ATOM 803 CB TRP A 187 −0.669 19.278 10.5861.00 31.40 C ATOM 804 CG TRP A 187 −0.339 17.955 9.756 1.00 33.36 C ATOM805 CD1 TRP A 187 −1.180 17.266 8.885 1.00 36.81 C ATOM 806 NE1 TRP A187 −0.563 16.136 8.391 1.00 37.42 N ATOM 807 CE2 TRP A 187 0.699 16.0838.919 1.00 38.06 C ATOM 808 CD2 TRP A 187 0.869 17.200 9.788 1.00 35.93C ATOM 809 CE3 TRP A 187 2.079 17.363 10.464 1.00 35.96 C ATOM 810 CZ3TRP A 187 3.041 16.448 10.268 1.00 38.27 C ATOM 811 CH2 TRP A 187 2.85715.350 9.386 1.00 37.53 C ATOM 812 CZ2 TRP A 187 1.676 15.149 8.721 1.0036.20 C ATOM 813 C TRP A 187 −0.753 20.517 8.387 1.00 29.83 C ATOM 814 OTRP A 187 0.135 20.246 7.539 1.00 27.61 O ATOM 815 N ASN A 188 −2.03720.751 8.078 1.00 28.16 N ATOM 816 CA ASN A 188 −2.521 20.755 6.679 1.0028.81 C ATOM 817 CB ASN A 188 −4.018 20.335 6.628 1.00 27.28 C ATOM 818CG ASN A 188 −4.189 18.844 6.447 1.00 27.85 C ATOM 819 OD1 ASN A 188−3.221 18.120 6.229 1.00 30.13 O ATOM 820 ND2 ASN A 188 −5.416 18.3676.562 1.00 25.16 N ATOM 821 C ASN A 188 −2.317 22.083 5.939 1.00 28.69 CATOM 822 O ASN A 188 −2.976 22.351 4.912 1.00 28.16 O ATOM 823 N ASP A189 −1.417 22.916 6.453 1.00 28.38 N ATOM 824 CA ASP A 189 −1.064 24.1865.841 1.00 29.63 C ATOM 825 CB ASP A 189 −0.361 23.927 4.472 1.00 30.44C ATOM 826 CG ASP A 189 0.978 23.255 4.654 1.00 34.49 C ATOM 827 OD1 ASPA 189 1.747 23.745 5.545 1.00 36.20 O ATOM 828 OD2 ASP A 189 1.21022.192 4.008 1.00 37.75 O ATOM 829 C ASP A 189 −2.195 25.185 5.706 1.0029.23 C ATOM 830 O ASP A 189 −2.196 26.026 4.788 1.00 29.61 O ATOM 831 NASN A 190 −3.161 25.105 6.622 1.00 28.19 N ATOM 832 CA ASN A 190 −4.15826.126 6.724 1.00 27.21 C ATOM 833 CB ASN A 190 −5.511 25.547 7.254 1.0025.60 C ATOM 834 CG ASN A 190 −6.073 24.485 6.339 1.00 24.16 C ATOM 835OD1 ASN A 190 −6.548 24.789 5.248 1.00 25.54 O ATOM 836 ND2 ASN A 190−5.995 23.233 6.751 1.00 22.44 N ATOM 837 C ASN A 190 −3.634 27.2157.618 1.00 27.62 C ATOM 838 O ASN A 190 −2.931 26.923 8.583 1.00 28.53 OATOM 839 N THR A 191 −4.001 28.457 7.307 1.00 28.23 N ATOM 840 CA THR A191 −3.761 29.597 8.193 1.00 28.87 C ATOM 841 CB THR A 191 −3.396 30.8337.361 1.00 29.15 C ATOM 842 OG1 THR A 191 −2.188 30.538 6.652 1.00 31.36O ATOM 843 CG2 THR A 191 −3.171 32.049 8.277 1.00 31.30 C ATOM 844 C THRA 191 −5.006 29.843 9.099 1.00 27.84 C ATOM 845 O THR A 191 −6.09630.157 8.622 1.00 27.93 O ATOM 846 N VAL A 192 −4.813 29.688 10.406 1.0028.14 N ATOM 847 CA VAL A 192 −5.905 29.719 11.400 1.00 27.77 C ATOM 848CB VAL A 192 −5.808 28.512 12.350 1.00 26.87 C ATOM 849 CG1 VAL A 192−7.022 28.475 13.300 1.00 27.00 C ATOM 850 CG2 VAL A 192 −5.690 27.16211.532 1.00 26.44 C ATOM 851 C VAL A 192 −5.905 31.048 12.235 1.00 29.05C ATOM 852 O VAL A 192 −4.876 31.468 12.806 1.00 29.85 O ATOM 853 N ARGA 193 −7.048 31.703 12.284 1.00 27.96 N ATOM 854 CA ARG A 193 −7.23332.827 13.169 1.00 29.69 C ATOM 855 CB ARG A 193 −7.559 34.100 12.3851.00 29.62 C ATOM 856 CG ARG A 193 −6.444 34.579 11.482 1.00 33.74 CATOM 857 CD ARG A 193 −6.956 35.638 10.516 1.00 41.01 C ATOM 858 NE ARGA 193 −5.825 36.233 9.767 1.00 50.62 N ATOM 859 CZ ARG A 193 −5.23835.718 8.668 1.00 53.47 C ATOM 860 NH1 ARG A 193 −5.633 34.559 8.1291.00 54.25 N ATOM 861 NH2 ARG A 193 −4.234 36.372 8.095 1.00 55.59 NATOM 862 C ARG A 193 −8.438 32.451 14.049 1.00 29.25 C ATOM 863 O ARG A193 −9.275 31.619 13.660 1.00 26.12 O ATOM 864 N VAL A 194 −8.523 33.08515.219 1.00 30.07 N ATOM 865 CA VAL A 194 −9.676 32.896 16.113 1.0029.06 C ATOM 866 CB VAL A 194 −9.270 32.162 17.470 1.00 31.71 C ATOM 867CG1 VAL A 194 −8.265 31.013 17.189 1.00 29.70 C ATOM 868 CG2 VAL A 194−8.693 33.093 18.509 1.00 29.72 C ATOM 869 C VAL A 194 −10.418 34.19516.316 1.00 28.87 C ATOM 870 O VAL A 194 −9.806 35.286 16.243 1.00 27.66O ATOM 871 N SER A 195 −11.728 34.104 16.556 1.00 27.12 N ATOM 872 CASER A 195 −12.581 35.299 16.612 1.00 26.89 C ATOM 873 CB SER A 195−14.036 34.898 16.873 1.00 27.31 C ATOM 874 OG SER A 195 −14.129 34.25718.174 1.00 25.66 O ATOM 875 C SER A 195 −12.115 36.220 17.747 1.0025.66 C ATOM 876 O SER A 195 −11.402 35.785 18.657 1.00 24.47 O ATOM 877N LYS A 196 −12.566 37.463 17.725 1.00 26.32 N ATOM 878 CA LYS A 196−12.108 38.399 18.767 1.00 27.97 C ATOM 879 CB LYS A 196 −12.581 39.81518.418 1.00 27.76 C ATOM 880 CG LYS A 196 −11.677 40.430 17.375 1.0034.20 C ATOM 881 CD LYS A 196 −12.432 41.396 16.488 1.00 42.92 C ATOM882 CE LYS A 196 −11.522 41.909 15.355 1.00 47.63 C ATOM 883 NZ LYS A196 −10.391 42.734 15.894 1.00 49.98 N ATOM 884 C LYS A 196 −12.63537.965 20.148 1.00 27.45 C ATOM 885 O LYS A 196 −11.968 38.176 21.1561.00 27.97 O ATOM 886 N THR A 197 −13.844 37.390 20.179 1.00 26.73 NATOM 887 CA THR A 197 −14.400 36.946 21.454 1.00 27.39 C ATOM 888 CB THRA 197 −15.880 36.620 21.372 1.00 27.32 C ATOM 889 OG1 THR A 197 −16.08335.558 20.440 1.00 28.59 O ATOM 890 CG2 THR A 197 −16.681 37.817 20.8911.00 27.51 C ATOM 891 C THR A 197 −13.644 35.749 21.981 1.00 27.16 CATOM 892 O THR A 197 −13.384 35.655 23.195 1.00 26.76 O ATOM 893 N LEU A198 −13.258 34.825 21.092 1.00 26.56 N ATOM 894 CA LEU A 198 −12.36133.734 21.518 1.00 26.73 C ATOM 895 CB LEU A 198 −12.098 32.702 20.3821.00 27.47 C ATOM 896 CG LEU A 198 −13.233 31.710 20.187 1.00 26.53 CATOM 897 CD1 LEU A 198 −12.970 30.817 18.963 1.00 29.55 C ATOM 898 CD2LEU A 198 −13.370 30.815 21.453 1.00 24.14 C ATOM 899 C LEU A 198−11.034 34.250 22.063 1.00 26.63 C ATOM 900 O LEU A 198 −10.534 33.72823.060 1.00 26.63 O ATOM 901 N GLN A 199 −10.459 35.262 21.421 1.0027.02 N ATOM 902 CA GLN A 199 −9.203 35.819 21.900 1.00 29.00 C ATOM 903CB GLN A 199 −8.696 36.933 20.987 1.00 29.92 C ATOM 904 CG GLN A 199−8.078 36.484 19.696 1.00 35.17 C ATOM 905 CD GLN A 199 −7.910 37.67718.755 1.00 42.65 C ATOM 906 OE1 GLN A 199 −7.473 38.789 19.167 1.0043.78 O ATOM 907 NE2 GLN A 199 −8.321 37.487 17.512 1.00 41.52 N ATOM908 C GLN A 199 −9.405 36.416 23.278 1.00 28.53 C ATOM 909 O GLN A 199−8.591 36.225 24.191 1.00 27.18 O ATOM 910 N ARG A 200 −10.498 37.15523.408 1.00 28.92 N ATOM 911 CA ARG A 200 −10.796 37.871 24.666 1.0027.60 C ATOM 912 CB ARG A 200 −12.077 38.707 24.481 1.00 28.09 C ATOM913 CG ARG A 200 −12.551 39.551 25.731 1.00 27.90 C ATOM 914 CD ARG A200 −13.718 40.446 25.377 1.00 26.48 C ATOM 915 NE ARG A 200 −13.27941.396 24.356 1.00 30.07 N ATOM 916 CZ ARG A 200 −13.768 41.476 23.1041.00 28.44 C ATOM 917 NH1 ARG A 200 −14.793 40.738 22.716 1.00 26.58 NATOM 918 NH2 ARG A 200 −13.232 42.345 22.237 1.00 28.69 N ATOM 919 C ARGA 200 −10.968 36.934 25.859 1.00 28.34 C ATOM 920 O ARG A 200 −10.49137.238 26.955 1.00 28.25 O ATOM 921 N PHE A 201 −11.706 35.848 25.6601.00 28.84 N ATOM 922 CA PHE A 201 −12.244 35.004 26.738 1.00 28.86 CATOM 923 CB PHE A 201 −13.772 34.828 26.559 1.00 28.35 C ATOM 924 CG PHEA 201 −14.568 36.097 26.766 1.00 25.52 C ATOM 925 CD1 PHE A 201 −14.55436.770 27.997 1.00 27.82 C ATOM 926 CE1 PHE A 201 −15.273 37.974 28.1661.00 27.90 C ATOM 927 CZ PHE A 201 −16.034 38.498 27.120 1.00 28.95 CATOM 928 CE2 PHE A 201 −16.063 37.831 25.899 1.00 27.66 C ATOM 929 CD2PHE A 201 −15.319 36.623 25.735 1.00 27.72 C ATOM 930 C PHE A 201−11.563 33.627 26.884 1.00 30.86 C ATOM 931 O PHE A 201 −11.721 32.96427.915 1.00 30.47 O ATOM 932 N ALA A 202 −10.780 33.200 25.895 1.0031.85 N ATOM 933 CA ALA A 202 −10.326 31.801 25.894 1.00 34.65 C ATOM934 CB ALA A 202 −11.347 30.904 25.154 1.00 32.12 C ATOM 935 C ALA A 202−8.924 31.544 25.367 1.00 37.14 C ATOM 936 O ALA A 202 −8.222 30.71525.921 1.00 38.77 O ATOM 937 N TRP A 203 −8.523 32.260 24.307 1.00 38.77N ATOM 938 CA TRP A 203 −7.316 31.934 23.527 1.00 40.33 C ATOM 939 CBTRP A 203 −7.720 31.335 22.174 1.00 38.58 C ATOM 940 CG TRP A 203 −6.61030.594 21.453 1.00 38.71 C ATOM 941 CD1 TRP A 203 −5.864 31.038 20.3701.00 37.42 C ATOM 942 NE1 TRP A 203 −4.978 30.057 19.965 1.00 37.40 NATOM 943 CE2 TRP A 203 −5.106 28.975 20.808 1.00 36.87 C ATOM 944 CD2TRP A 203 −6.134 29.284 21.754 1.00 36.44 C ATOM 945 CE3 TRP A 203−6.459 28.335 22.740 1.00 38.19 C ATOM 946 CZ3 TRP A 203 −5.762 27.09022.750 1.00 37.22 C ATOM 947 CH2 TRP A 203 −4.749 26.813 21.786 1.0036.78 C ATOM 948 CZ2 TRP A 203 −4.406 27.742 20.821 1.00 36.69 C ATOM949 C TRP A 203 −6.525 33.207 23.251 1.00 42.00 C ATOM 950 O TRP A 203−6.552 33.692 22.103 1.00 44.02 O ATOM 951 OXT TRP A 203 −5.876 33.79724.117 1.00 42.42 O ATOM 952 N PRO B 85 7.442 25.386 −43.697 1.00 62.33N ATOM 953 CA PRO B 85 8.153 26.040 −42.594 1.00 61.88 C ATOM 954 CB PROB 85 7.082 26.935 −41.948 1.00 62.07 C ATOM 955 CG PRO B 85 6.069 27.170−43.026 1.00 62.66 C ATOM 956 CD PRO B 85 6.075 25.911 −43.875 1.0062.82 C ATOM 957 C PRO B 85 8.678 25.031 −41.572 1.00 60.95 C ATOM 958 OPRO B 85 7.988 24.045 −41.269 1.00 61.39 O ATOM 959 N ALA B 86 9.89325.269 −41.064 1.00 59.55 N ATOM 960 CA ALA B 86 10.476 24.427 −40.0261.00 58.13 C ATOM 961 CB ALA B 86 11.886 24.854 −39.737 1.00 58.01 CATOM 962 C ALA B 86 9.618 24.453 −38.750 1.00 57.61 C ATOM 963 O ALA B86 8.875 25.413 −38.517 1.00 57.45 O ATOM 964 N SER B 87 9.699 23.382−37.955 1.00 56.80 N ATOM 965 CA SER B 87 9.094 23.341 −36.621 1.0055.97 C ATOM 966 CB SER B 87 9.578 22.115 −35.841 1.00 56.09 C ATOM 967OG SER B 87 9.096 20.914 −36.416 1.00 59.57 O ATOM 968 C SER B 87 9.50424.568 −35.832 1.00 54.53 C ATOM 969 O SER B 87 10.638 25.044 −35.9521.00 53.79 O ATOM 970 N ARG B 88 8.587 25.081 −35.022 1.00 53.11 N ATOM971 CA ARG B 88 8.994 26.013 −33.978 1.00 51.52 C ATOM 972 CB ARG B 888.504 27.432 −34.252 1.00 52.04 C ATOM 973 CG ARG B 88 7.041 27.550−34.529 1.00 54.33 C ATOM 974 CD ARG B 88 6.728 28.924 −35.062 1.0057.93 C ATOM 975 NE ARG B 88 5.363 29.328 −34.759 1.00 60.15 N ATOM 976CZ ARG B 88 5.012 30.052 −33.699 1.00 63.10 C ATOM 977 NH1 ARG B 885.932 30.458 −32.815 1.00 62.43 N ATOM 978 NH2 ARG B 88 3.730 30.373−33.519 1.00 62.59 N ATOM 979 C ARG B 88 8.537 25.490 −32.617 1.00 49.39C ATOM 980 O ARG B 88 7.619 24.684 −32.550 1.00 47.87 O ATOM 981 N TYR B89 9.217 25.943 −31.567 1.00 47.24 N ATOM 982 CA TYR B 89 8.982 25.477−30.204 1.00 45.49 C ATOM 983 CB TYR B 89 10.298 25.132 −29.498 1.0046.96 C ATOM 984 CG TYR B 89 10.938 23.840 −29.949 1.00 49.23 C ATOM 985CD1 TYR B 89 12.003 23.859 −30.844 1.00 51.93 C ATOM 986 CE1 TYR B 8912.614 22.678 −31.274 1.00 53.21 C ATOM 987 CZ TYR B 89 12.159 21.453−30.800 1.00 52.97 C ATOM 988 OH TYR B 89 12.793 20.295 −31.238 1.0052.46 O ATOM 989 CE2 TYR B 89 11.089 21.403 −29.901 1.00 51.87 C ATOM990 CD2 TYR B 89 10.485 22.596 −29.482 1.00 50.16 C ATOM 991 C TYR B 898.251 26.525 −29.391 1.00 43.03 C ATOM 992 O TYR B 89 8.599 27.718−29.405 1.00 42.37 O ATOM 993 N ILE B 90 7.230 26.066 −28.685 1.00 39.81N ATOM 994 CA ILE B 90 6.552 26.883 −27.712 1.00 37.00 C ATOM 995 CB ILEB 90 5.018 26.620 −27.746 1.00 37.76 C ATOM 996 CG1 ILE B 90 4.41426.837 −29.163 1.00 37.36 C ATOM 997 CD1 ILE B 90 4.795 28.145 −29.8621.00 39.19 C ATOM 998 CG2 ILE B 90 4.317 27.434 −26.660 1.00 34.76 CATOM 999 C ILE B 90 7.120 26.456 −26.366 1.00 36.01 C ATOM 1000 O ILE B90 7.290 25.244 −26.111 1.00 34.34 O ATOM 1001 N THR B 91 7.455 27.422−25.516 1.00 35.22 N ATOM 1002 CA THR B 91 8.016 27.093 −24.204 1.0035.55 C ATOM 1003 CB THR B 91 9.552 27.381 −24.113 1.00 36.05 C ATOM1004 OG1 THR B 91 9.811 28.768 −24.427 1.00 37.96 O ATOM 1005 CG2 THR B91 10.350 26.466 −25.020 1.00 37.46 C ATOM 1006 C THR B 91 7.286 27.902−23.156 1.00 35.72 C ATOM 1007 O THR B 91 7.699 29.018 −22.827 1.0035.37 O ATOM 1008 N ASP B 92 6.161 27.373 −22.666 1.00 35.05 N ATOM 1009CA ASP B 92 5.366 28.077 −21.650 1.00 33.77 C ATOM 1010 CB ASP B 924.034 27.364 −21.361 1.00 33.89 C ATOM 1011 CG ASP B 92 2.992 27.502−22.482 1.00 34.60 C ATOM 1012 OD1 ASP B 92 3.154 28.326 −23.431 1.0035.61 O ATOM 1013 OD2 ASP B 92 1.975 26.774 −22.383 1.00 33.13 O ATOM1014 C ASP B 92 6.146 28.082 −20.349 1.00 33.53 C ATOM 1015 O ASP B 926.056 29.033 −19.578 1.00 33.40 O ATOM 1016 N MET B 93 6.878 27.009−20.083 1.00 32.58 N ATOM 1017 CA MET B 93 7.539 26.857 −18.794 1.0032.30 C ATOM 1018 CB MET B 93 7.607 25.369 −18.402 1.00 32.52 C ATOM1019 CG MET B 93 6.322 24.773 −17.914 1.00 29.43 C ATOM 1020 SD MET B 936.429 23.054 −17.472 1.00 28.89 S ATOM 1021 CE MET B 93 5.883 22.183−18.940 1.00 26.92 C ATOM 1022 C MET B 93 8.983 27.427 −18.831 1.0034.01 C ATOM 1023 O MET B 93 9.657 27.323 −19.864 1.00 32.66 O ATOM 1024N THR B 94 9.457 27.980 −17.704 1.00 34.20 N ATOM 1025 CA THR B 9410.880 28.311 −17.544 1.00 35.22 C ATOM 1026 CB THR B 94 11.120 29.178−16.266 1.00 36.09 C ATOM 1027 OG1 THR B 94 10.674 28.440 −15.134 1.0036.40 O ATOM 1028 CG2 THR B 94 10.354 30.513 −16.315 1.00 35.20 C ATOM1029 C THR B 94 11.727 27.047 −17.428 1.00 34.67 C ATOM 1030 O THR B 9411.199 25.961 −17.197 1.00 33.47 O ATOM 1031 N ILE B 95 13.051 27.175−17.583 1.00 35.62 N ATOM 1032 CA ILE B 95 13.960 26.054 −17.369 1.0036.37 C ATOM 1033 CB ILE B 95 15.499 26.465 −17.487 1.00 36.16 C ATOM1034 CG1 ILE B 95 15.815 26.979 −18.895 1.00 39.79 C ATOM 1035 CD1 ILE B95 17.240 27.642 −19.070 1.00 39.32 C ATOM 1036 CG2 ILE B 95 16.34325.262 −17.243 1.00 36.87 C ATOM 1037 C ILE B 95 13.739 25.427 −15.9981.00 35.94 C ATOM 1038 O ILE B 95 13.831 24.194 −15.836 1.00 36.49 OATOM 1039 N GLU B 96 13.509 26.257 −14.993 1.00 36.30 N ATOM 1040 CA GLUB 96 13.309 25.726 −13.628 1.00 37.91 C ATOM 1041 CB GLU B 96 13.37226.878 −12.596 1.00 38.48 C ATOM 1042 CG GLU B 96 13.421 26.440 −11.1341.00 41.71 C ATOM 1043 CD GLU B 96 12.042 26.159 −10.555 1.00 45.38 CATOM 1044 OE1 GLU B 96 11.042 26.752 −11.042 1.00 47.09 O ATOM 1045 OE2GLU B 96 11.967 25.354 −9.600 1.00 46.98 O ATOM 1046 C GLU B 96 11.99524.913 −13.517 1.00 36.88 C ATOM 1047 O GLU B 96 11.977 23.805 −12.9971.00 36.45 O ATOM 1048 N GLU B 97 10.909 25.477 −14.028 1.00 36.87 NATOM 1049 CA GLU B 97 9.602 24.789 −14.010 1.00 36.88 C ATOM 1050 CB GLUB 97 8.552 25.667 −14.663 1.00 36.11 C ATOM 1051 CG GLU B 97 8.17726.883 −13.781 1.00 38.37 C ATOM 1052 CD GLU B 97 7.264 27.884 −14.4521.00 38.94 C ATOM 1053 OE1 GLU B 97 7.424 28.160 −15.681 1.00 38.42 OATOM 1054 OE2 GLU B 97 6.399 28.435 −13.725 1.00 41.47 O ATOM 1055 C GLUB 97 9.662 23.414 −14.664 1.00 36.23 C ATOM 1056 O GLU B 97 9.071 22.443−14.171 1.00 36.44 O ATOM 1057 N LEU B 98 10.409 23.313 −15.760 1.0035.44 N ATOM 1058 CA LEU B 98 10.447 22.090 −16.543 1.00 36.09 C ATOM1059 CB LEU B 98 10.992 22.400 −17.941 1.00 37.24 C ATOM 1060 CG LEU B98 10.961 21.395 −19.103 1.00 41.62 C ATOM 1061 CD1 LEU B 98 9.58721.306 −19.833 1.00 41.32 C ATOM 1062 CD2 LEU B 98 12.004 21.864 −20.0951.00 45.35 C ATOM 1063 C LEU B 98 11.290 21.025 −15.870 1.00 36.56 CATOM 1064 O LEU B 98 11.003 19.822 −15.985 1.00 35.75 O ATOM 1065 N SERB 99 12.322 21.470 −15.156 1.00 37.20 N ATOM 1066 CA SER B 99 13.29420.563 −14.547 1.00 38.65 C ATOM 1067 CB SER B 99 14.666 21.226 −14.5251.00 39.66 C ATOM 1068 OG SER B 99 14.626 22.393 −13.710 1.00 45.01 OATOM 1069 C SER B 99 12.934 20.161 −13.136 1.00 37.67 C ATOM 1070 O SERB 99 13.387 19.139 −12.682 1.00 37.38 O ATOM 1071 N ARG B 100 12.10120.962 −12.457 1.00 38.83 N ATOM 1072 CA ARG B 100 11.673 20.677 −11.0711.00 38.07 C ATOM 1073 CB ARG B 100 10.594 21.675 −10.658 1.00 39.03 CATOM 1074 CG ARG B 100 10.454 21.834 −9.166 1.00 40.88 C ATOM 1075 CDARG B 100 9.310 22.774 −8.836 1.00 40.98 C ATOM 1076 NE ARG B 100 9.42324.092 −9.464 1.00 39.64 N ATOM 1077 CZ ARG B 100 8.392 24.898 −9.6441.00 40.56 C ATOM 1078 NH1 ARG B 100 7.189 24.515 −9.231 1.00 44.30 NATOM 1079 NH2 ARG B 100 8.550 26.090 −10.198 1.00 42.36 N ATOM 1080 CARG B 100 11.121 19.261 −10.945 1.00 37.43 C ATOM 1081 O ARG B 10010.438 18.783 −11.846 1.00 36.57 O ATOM 1082 N ASP B 101 11.453 18.564−9.860 1.00 35.80 N ATOM 1083 CA ASP B 101 10.742 17.342 −9.523 1.0035.10 C ATOM 1084 CB ASP B 101 11.651 16.271 −8.899 1.00 35.75 C ATOM1085 CG ASP B 101 12.806 15.834 −9.812 1.00 37.07 C ATOM 1086 OD1 ASP B101 12.570 15.518 −11.012 1.00 35.64 O ATOM 1087 OD2 ASP B 101 13.95215.733 −9.275 1.00 38.34 O ATOM 1088 C ASP B 101 9.690 17.753 −8.5001.00 34.47 C ATOM 1089 O ASP B 101 9.912 18.665 −7.681 1.00 35.01 O ATOM1090 N TRP B 102 8.540 17.093 −8.525 1.00 33.32 N ATOM 1091 CA TRP B 1027.468 17.502 −7.641 1.00 31.72 C ATOM 1092 CB TRP B 102 6.491 18.411−8.419 1.00 32.70 C ATOM 1093 CG TRP B 102 5.866 17.687 −9.554 1.0030.91 C ATOM 1094 CD1 TRP B 102 6.433 17.389 −10.754 1.00 31.44 C ATOM1095 NE1 TRP B 102 5.544 16.652 −11.540 1.00 33.38 N ATOM 1096 CE2 TRP B102 4.386 16.454 −10.833 1.00 34.03 C ATOM 1097 CD2 TRP B 102 4.56217.079 −9.552 1.00 34.03 C ATOM 1098 CE3 TRP B 102 3.512 17.033 −8.6201.00 33.01 C ATOM 1099 CZ3 TRP B 102 2.309 16.373 −8.993 1.00 30.04 CATOM 1100 CH2 TRP B 102 2.188 15.734 −10.255 1.00 31.03 C ATOM 1101 CZ2TRP B 102 3.206 15.764 −11.184 1.00 31.94 C ATOM 1102 C TRP B 102 6.82916.320 −6.880 1.00 31.64 C ATOM 1103 O TRP B 102 7.038 15.140 −7.2091.00 31.20 O ATOM 1104 N PHE B 103 6.114 16.653 −5.800 1.00 30.85 N ATOM1105 CA PHE B 103 5.628 15.684 −4.827 1.00 29.60 C ATOM 1106 CB PHE B103 6.029 16.180 −3.425 1.00 30.18 C ATOM 1107 CG PHE B 103 5.321 15.507−2.268 1.00 31.54 C ATOM 1108 CD1 PHE B 103 5.742 14.284 −1.798 1.0031.56 C ATOM 1109 CE1 PHE B 103 5.122 13.681 −0.692 1.00 30.41 C ATOM1110 CZ PHE B 103 4.055 14.329 −0.046 1.00 31.78 C ATOM 1111 CE2 PHE B103 3.635 15.599 −0.483 1.00 30.83 C ATOM 1112 CD2 PHE B 103 4.27316.174 −1.597 1.00 33.14 C ATOM 1113 C PHE B 103 4.118 15.612 −4.9351.00 27.88 C ATOM 1114 O PHE B 103 3.473 16.646 −5.063 1.00 28.45 O ATOM1115 N MET B 104 3.598 14.391 −4.875 1.00 27.19 N ATOM 1116 CA MET B 1042.163 14.120 −4.772 1.00 27.44 C ATOM 1117 CB MET B 104 1.715 13.163−5.899 1.00 26.04 C ATOM 1118 CG MET B 104 1.798 13.758 −7.355 1.0028.37 C ATOM 1119 SD MET B 104 1.632 12.389 −8.528 1.00 26.62 S ATOM1120 CE MET B 104 3.295 11.830 −8.571 1.00 26.34 C ATOM 1121 C MET B 1041.913 13.456 −3.389 1.00 27.60 C ATOM 1122 O MET B 104 2.502 12.434−3.068 1.00 26.49 O ATOM 1123 N LEU B 105 1.056 14.072 −2.583 1.00 26.42N ATOM 1124 CA LEU B 105 0.616 13.447 −1.317 1.00 26.58 C ATOM 1125 CBLEU B 105 −0.240 14.454 −0.508 1.00 25.53 C ATOM 1126 CG LEU B 105−0.660 14.024 0.917 1.00 28.52 C ATOM 1127 CD1 LEU B 105 0.620 13.7821.774 1.00 26.80 C ATOM 1128 CD2 LEU B 105 −1.509 15.149 1.416 1.0028.79 C ATOM 1129 C LEU B 105 −0.185 12.189 −1.571 1.00 26.02 C ATOM1130 O LEU B 105 −0.030 11.227 −0.858 1.00 26.32 O ATOM 1131 N MET B 106−1.086 12.213 −2.572 1.00 26.57 N ATOM 1132 CA MET B 106 −1.909 11.043−2.919 1.00 25.33 C ATOM 1133 CB MET B 106 −3.414 11.381 −2.722 1.0024.16 C ATOM 1134 CG MET B 106 −3.718 11.818 −1.267 1.00 27.74 C ATOM1135 SD MET B 106 −5.495 12.138 −1.007 1.00 25.66 S ATOM 1136 CE MET B106 −5.818 10.701 0.032 1.00 35.03 C ATOM 1137 C MET B 106 −1.641 10.741−4.397 1.00 26.10 C ATOM 1138 O MET B 106 −2.439 11.106 −5.263 1.0024.95 O ATOM 1139 N PRO B 107 −0.515 10.079 −4.684 1.00 27.23 N ATOM1140 CA PRO B 107 −0.083 9.969 −6.107 1.00 26.85 C ATOM 1141 CB PRO B107 1.220 9.184 −6.024 1.00 26.93 C ATOM 1142 CG PRO B 107 1.622 9.205−4.482 1.00 26.97 C ATOM 1143 CD PRO B 107 0.333 9.284 −3.763 1.00 26.75C ATOM 1144 C PRO B 107 −1.085 9.168 −6.958 1.00 26.73 C ATOM 1145 O PROB 107 −1.699 8.178 −6.490 1.00 26.39 O ATOM 1146 N LYS B 108 −1.2389.625 −8.202 1.00 27.58 N ATOM 1147 CA LYS B 108 −2.047 8.964 −9.2081.00 28.66 C ATOM 1148 CB LYS B 108 −3.361 9.741 −9.422 1.00 28.49 CATOM 1149 CG LYS B 108 −4.375 9.513 −8.277 1.00 28.11 C ATOM 1150 CD LYSB 108 −4.773 8.044 −8.260 1.00 30.78 C ATOM 1151 CE LYS B 108 −5.3007.575 −6.971 1.00 32.01 C ATOM 1152 NZ LYS B 108 −4.282 7.664 −5.9061.00 33.62 N ATOM 1153 C LYS B 108 −1.212 9.009 −10.485 1.00 28.71 CATOM 1154 O LYS B 108 −0.620 10.034 −10.802 1.00 28.16 O ATOM 1155 N GLNB 109 −1.132 7.879 −11.171 1.00 30.52 N ATOM 1156 CA GLN B 109 −0.3737.809 −12.435 1.00 33.68 C ATOM 1157 CB GLN B 109 1.078 7.372 −12.1871.00 34.23 C ATOM 1158 CG GLN B 109 1.943 7.302 −13.432 1.00 39.99 CATOM 1159 CD GLN B 109 3.272 6.642 −13.153 1.00 47.20 C ATOM 1160 OE1GLN B 109 4.126 7.218 −12.489 1.00 52.68 O ATOM 1161 NE2 GLN B 109 3.4485.416 −13.636 1.00 51.24 N ATOM 1162 C GLN B 109 −1.066 6.845 −13.3521.00 34.01 C ATOM 1163 O GLN B 109 −1.408 5.722 −12.931 1.00 34.27 OATOM 1164 N LYS B 110 −1.283 7.290 −14.595 1.00 34.52 N ATOM 1165 CA LYSB 110 −1.941 6.463 −15.617 1.00 35.64 C ATOM 1166 CB LYS B 110 −3.3187.045 −15.923 1.00 35.09 C ATOM 1167 CG LYS B 110 −4.199 6.200 −16.7991.00 36.36 C ATOM 1168 CD LYS B 110 −5.256 7.078 −17.360 1.00 37.52 CATOM 1169 CE LYS B 110 −6.197 6.331 −18.301 1.00 43.96 C ATOM 1170 NZLYS B 110 −6.738 5.149 −17.583 1.00 45.73 N ATOM 1171 C LYS B 110 −1.0736.512 −16.889 1.00 35.81 C ATOM 1172 O LYS B 110 −0.677 7.581 −17.3061.00 34.99 O ATOM 1173 N VAL B 111 −0.765 5.344 −17.453 1.00 36.14 NATOM 1174 CA VAL B 111 −0.183 5.256 −18.790 1.00 37.37 C ATOM 1175 CBVAL B 111 0.595 3.969 −18.988 1.00 38.40 C ATOM 1176 CG1 VAL B 111 1.0963.874 −20.451 1.00 40.21 C ATOM 1177 CG2 VAL B 111 1.746 3.934 −18.0251.00 39.38 C ATOM 1178 C VAL B 111 −1.329 5.314 −19.766 1.00 37.36 CATOM 1179 O VAL B 111 −2.230 4.493 −19.737 1.00 37.69 O ATOM 1180 N GLUB 112 −1.367 6.331 −20.596 1.00 36.83 N ATOM 1181 CA GLU B 112 −2.4366.329 −21.550 1.00 37.26 C ATOM 1182 CB GLU B 112 −3.334 7.501 −21.2901.00 37.53 C ATOM 1183 CG GLU B 112 −4.730 7.186 −21.687 1.00 42.45 CATOM 1184 CD GLU B 112 −5.518 8.434 −21.769 1.00 47.91 C ATOM 1185 OE1GLU B 112 −6.665 8.423 −21.268 1.00 49.77 O ATOM 1186 OE2 GLU B 112−4.951 9.421 −22.317 1.00 47.40 O ATOM 1187 C GLU B 112 −1.915 6.361−22.986 1.00 36.04 C ATOM 1188 O GLU B 112 −1.497 7.415 −23.484 1.0034.78 O ATOM 1189 N GLY B 113 −1.920 5.204 −23.644 1.00 35.37 N ATOM1190 CA GLY B 113 −1.239 5.135 −24.935 1.00 33.99 C ATOM 1191 C GLY B113 0.262 5.420 −24.706 1.00 32.46 C ATOM 1192 O GLY B 113 0.895 4.810−23.819 1.00 33.59 O ATOM 1193 N PRO B 114 0.842 6.341 −25.484 1.0030.86 N ATOM 1194 CA PRO B 114 2.254 6.728 −25.432 1.00 30.15 C ATOM1195 CB PRO B 114 2.491 7.285 −26.845 1.00 30.38 C ATOM 1196 CG PRO B114 1.188 7.915 −27.171 1.00 30.21 C ATOM 1197 CD PRO B 114 0.128 7.066−26.553 1.00 31.78 C ATOM 1198 C PRO B 114 2.584 7.817 −24.386 1.0028.89 C ATOM 1199 O PRO B 114 3.733 8.284 −24.323 1.00 27.26 O ATOM 1200N LEU B 115 1.603 8.178 −23.538 1.00 27.32 N ATOM 1201 CA LEU B 1151.751 9.275 −22.578 1.00 27.63 C ATOM 1202 CB LEU B 115 0.833 10.464−22.938 1.00 26.73 C ATOM 1203 CG LEU B 115 0.951 11.005 −24.372 1.0028.81 C ATOM 1204 CD1 LEU B 115 −0.120 12.044 −24.555 1.00 28.14 C ATOM1205 CD2 LEU B 115 2.323 11.667 −24.558 1.00 27.61 C ATOM 1206 C LEU B115 1.456 8.803 −21.149 1.00 27.69 C ATOM 1207 O LEU B 115 0.695 7.849−20.937 1.00 28.97 O ATOM 1208 N CYS B 116 2.077 9.493 −20.204 1.0028.03 N ATOM 1209 CA CYS B 116 1.923 9.240 −18.787 1.00 27.99 C ATOM1210 CB CYS B 116 3.288 8.988 −18.165 1.00 28.84 C ATOM 1211 SG CYS B116 3.202 8.685 −16.342 1.00 32.13 S ATOM 1212 C CYS B 116 1.275 10.452−18.147 1.00 28.28 C ATOM 1213 O CYS B 116 1.700 11.596 −18.392 1.0027.83 O ATOM 1214 N ILE B 117 0.204 10.204 −17.354 1.00 27.49 N ATOM1215 CA ILE B 117 −0.572 11.279 −16.710 1.00 26.02 C ATOM 1216 CB ILE B117 −2.093 11.221 −17.073 1.00 26.73 C ATOM 1217 CG1 ILE B 117 −2.26211.134 −18.605 1.00 27.69 C ATOM 1218 CD1 ILE B 117 −3.458 10.398−19.049 1.00 28.54 C ATOM 1219 CG2 ILE B 117 −2.878 12.453 −16.465 1.0025.95 C ATOM 1220 C ILE B 117 −0.391 11.052 −15.192 1.00 24.22 C ATOM1221 O ILE B 117 −0.574 9.957 −14.719 1.00 26.21 O ATOM 1222 N ARG B 1180.002 12.093 −14.495 1.00 24.83 N ATOM 1223 CA ARG B 118 0.151 12.069−13.050 1.00 24.60 C ATOM 1224 CB ARG B 118 1.625 12.324 −12.676 1.0026.12 C ATOM 1225 CG ARG B 118 2.554 11.240 −13.053 1.00 29.98 C ATOM1226 CD ARG B 118 3.976 11.644 −12.680 1.00 36.27 C ATOM 1227 NE ARG B118 4.833 10.487 −12.835 1.00 43.72 N ATOM 1228 CZ ARG B 118 5.73910.363 −13.792 1.00 48.66 C ATOM 1229 NH1 ARG B 118 5.935 11.371 −14.6541.00 50.62 N ATOM 1230 NH2 ARG B 118 6.456 9.235 −13.879 1.00 50.32 NATOM 1231 C ARG B 118 −0.648 13.195 −12.465 1.00 23.69 C ATOM 1232 O ARGB 118 −0.738 14.276 −13.030 1.00 22.96 O ATOM 1233 N ILE B 119 −1.17012.992 −11.254 1.00 24.51 N ATOM 1234 CA ILE B 119 −1.918 14.071 −10.6301.00 23.38 C ATOM 1235 CB ILE B 119 −3.379 14.189 −11.220 1.00 25.08 CATOM 1236 CG1 ILE B 119 −4.168 15.391 −10.625 1.00 24.01 C ATOM 1237 CD1ILE B 119 −5.698 15.456 −11.077 1.00 24.74 C ATOM 1238 CG2 ILE B 119−4.097 12.864 −11.167 1.00 26.19 C ATOM 1239 C ILE B 119 −1.927 13.744−9.149 1.00 22.60 C ATOM 1240 O ILE B 119 −1.861 12.601 −8.768 1.0023.10 O ATOM 1241 N ASP B 120 −1.893 14.786 −8.349 1.00 22.84 N ATOM1242 CA ASP B 120 −2.059 14.611 −6.892 1.00 24.58 C ATOM 1243 CB ASP B120 −1.358 15.710 −6.147 1.00 23.29 C ATOM 1244 CG ASP B 120 −1.25215.431 −4.633 1.00 25.72 C ATOM 1245 OD1 ASP B 120 −1.856 14.473 −4.1361.00 26.52 O ATOM 1246 OD2 ASP B 120 −0.495 16.173 −3.961 1.00 27.39 OATOM 1247 C ASP B 120 −3.561 14.713 −6.580 1.00 22.94 C ATOM 1248 O ASPB 120 −4.145 15.773 −6.725 1.00 23.18 O ATOM 1249 N GLN B 121 −4.12713.597 −6.196 1.00 23.75 N ATOM 1250 CA GLN B 121 −5.534 13.493 −5.7181.00 24.41 C ATOM 1251 CB GLN B 121 −5.888 12.008 −5.498 1.00 23.59 CATOM 1252 CG GLN B 121 −7.357 11.742 −4.999 1.00 24.61 C ATOM 1253 CDGLN B 121 −7.689 10.313 −4.820 1.00 25.20 C ATOM 1254 OE1 GLN B 121−6.826 9.468 −4.792 1.00 24.43 O ATOM 1255 NE2 GLN B 121 −8.996 10.017−4.688 1.00 28.25 N ATOM 1256 C GLN B 121 −5.863 14.386 −4.487 1.0024.49 C ATOM 1257 O GLN B 121 −7.026 14.736 −4.267 1.00 24.40 O ATOM1258 N ALA B 122 −4.842 14.834 −3.740 1.00 25.85 N ATOM 1259 CA ALA B122 −5.058 15.623 −2.509 1.00 24.80 C ATOM 1260 CB ALA B 122 −3.81315.587 −1.658 1.00 25.27 C ATOM 1261 C ALA B 122 −5.372 17.049 −2.8461.00 25.48 C ATOM 1262 O ALA B 122 −5.871 17.837 −2.014 1.00 23.88 OATOM 1263 N ILE B 123 −5.033 17.457 −4.065 1.00 25.50 N ATOM 1264 CA ILEB 123 −5.136 18.876 −4.370 1.00 26.71 C ATOM 1265 CB ILE B 123 −4.08819.273 −5.469 1.00 27.03 C ATOM 1266 CG1 ILE B 123 −2.664 19.148 −4.8951.00 28.82 C ATOM 1267 CD1 ILE B 123 −2.252 20.255 −3.962 1.00 28.25 CATOM 1268 CG2 ILE B 123 −4.368 20.704 −6.006 1.00 29.25 C ATOM 1269 CILE B 123 −6.541 19.345 −4.791 1.00 28.30 C ATOM 1270 O ILE B 123 −7.11418.843 −5.810 1.00 28.00 O ATOM 1271 N MET B 124 −7.059 20.359 −4.0721.00 27.99 N ATOM 1272 CA MET B 124 −8.433 20.849 −4.267 1.00 30.20 CATOM 1273 CB MET B 124 −9.407 20.226 −3.257 1.00 28.85 C ATOM 1274 CGMET B 124 −9.245 18.768 −3.159 1.00 30.84 C ATOM 1275 SD MET B 124−10.621 18.153 −2.165 1.00 33.91 S ATOM 1276 CE MET B 124 −10.006 16.631−1.750 1.00 24.31 C ATOM 1277 C MET B 124 −8.505 22.326 −4.146 1.0031.04 C ATOM 1278 O MET B 124 −7.600 22.948 −3.608 1.00 31.15 O ATOM1279 N ASP B 125 −9.577 22.892 −4.694 1.00 33.33 N ATOM 1280 CA ASP B125 −9.940 24.291 −4.503 1.00 34.92 C ATOM 1281 CB ASP B 125 −10.26924.509 −3.012 1.00 36.08 C ATOM 1282 CG ASP B 125 −11.451 23.718 −2.5791.00 38.58 C ATOM 1283 OD1 ASP B 125 −12.498 23.851 −3.285 1.00 46.09 OATOM 1284 OD2 ASP B 125 −11.342 22.965 −1.572 1.00 41.80 O ATOM 1285 CASP B 125 −8.930 25.325 −4.949 1.00 35.72 C ATOM 1286 O ASP B 125 −8.95826.442 −4.455 1.00 36.05 O ATOM 1287 N LYS B 126 −8.045 24.987 −5.8801.00 34.36 N ATOM 1288 CA LYS B 126 −7.079 25.938 −6.355 1.00 34.46 CATOM 1289 CB LYS B 126 −5.654 25.347 −6.229 1.00 35.61 C ATOM 1290 CGLYS B 126 −5.123 25.518 −4.749 1.00 35.45 C ATOM 1291 CD LYS B 126−4.231 24.371 −4.247 1.00 41.21 C ATOM 1292 CE LYS B 126 −4.235 24.232−2.709 1.00 40.11 C ATOM 1293 NZ LYS B 126 −5.023 23.010 −2.047 1.0039.60 N ATOM 1294 C LYS B 126 −7.410 26.445 −7.763 1.00 35.16 C ATOM1295 O LYS B 126 −8.172 25.801 −8.495 1.00 34.91 O ATOM 1296 N ASN B 127−6.917 27.635 −8.091 1.00 34.53 N ATOM 1297 CA ASN B 127 −6.852 28.104−9.463 1.00 35.83 C ATOM 1298 CB ASN B 127 −6.784 29.634 −9.482 1.0036.09 C ATOM 1299 CG ASN B 127 −8.059 30.259 −8.963 1.00 39.59 C ATOM1300 OD1 ASN B 127 −9.151 29.895 −9.403 1.00 42.15 O ATOM 1301 ND2 ASN B127 −7.935 31.181 −8.010 1.00 41.71 N ATOM 1302 C ASN B 127 −5.60827.460 −10.123 1.00 35.83 C ATOM 1303 O ASN B 127 −4.471 27.660 −9.6461.00 35.54 O ATOM 1304 N ILE B 128 −5.838 26.643 −11.153 1.00 34.49 NATOM 1305 CA ILE B 128 −4.762 25.838 −11.739 1.00 34.62 C ATOM 1306 CBILE B 128 −5.119 24.306 −11.680 1.00 34.79 C ATOM 1307 CG1 ILE B 128−5.265 23.784 −10.233 1.00 32.44 C ATOM 1308 CD1 ILE B 128 −3.957 23.744−9.465 1.00 36.65 C ATOM 1309 CG2 ILE B 128 −4.116 23.458 −12.496 1.0033.81 C ATOM 1310 C ILE B 128 −4.571 26.280 −13.192 1.00 34.82 C ATOM1311 O ILE B 128 −5.550 26.529 −13.892 1.00 35.00 O ATOM 1312 N MET B129 −3.314 26.404 −13.643 1.00 35.61 N ATOM 1313 CA MET B 129 −2.99626.814 −15.021 1.00 34.86 C ATOM 1314 CB MET B 129 −2.261 28.179 −15.0481.00 35.13 C ATOM 1315 CG MET B 129 −1.751 28.640 −16.447 1.00 35.56 CATOM 1316 SD MET B 129 −3.035 29.030 −17.670 1.00 38.68 S ATOM 1317 CEMET B 129 −3.538 30.686 −17.157 1.00 41.92 C ATOM 1318 C MET B 129−2.130 25.742 −15.712 1.00 34.42 C ATOM 1319 O MET B 129 −1.032 25.415−15.221 1.00 33.25 O ATOM 1320 N LEU B 130 −2.612 25.201 −16.832 1.0033.00 N ATOM 1321 CA LEU B 130 −1.798 24.222 −17.574 1.00 32.79 C ATOM1322 CB LEU B 130 −2.667 23.270 −18.395 1.00 33.33 C ATOM 1323 CG LEU B130 −3.805 22.507 −17.746 1.00 34.39 C ATOM 1324 CD1 LEU B 130 −4.21821.298 −18.640 1.00 35.78 C ATOM 1325 CD2 LEU B 130 −3.454 22.026−16.355 1.00 33.03 C ATOM 1326 C LEU B 130 −0.867 25.000 −18.501 1.0031.81 C ATOM 1327 O LEU B 130 −1.316 25.839 −19.251 1.00 31.56 O ATOM1328 N LYS B 131 0.425 24.706 −18.407 1.00 31.06 N ATOM 1329 CA LYS B131 1.487 25.276 −19.233 1.00 30.62 C ATOM 1330 CB LYS B 131 2.46526.072 −18.367 1.00 31.05 C ATOM 1331 CG LYS B 131 1.907 27.398 −17.9441.00 33.09 C ATOM 1332 CD LYS B 131 2.876 28.133 −17.055 1.00 35.17 CATOM 1333 CE LYS B 131 2.199 29.374 −16.485 1.00 38.38 C ATOM 1334 NZLYS B 131 3.249 30.258 −15.877 1.00 39.16 N ATOM 1335 C LYS B 131 2.21524.125 −19.926 1.00 29.36 C ATOM 1336 O LYS B 131 2.375 23.043 −19.3651.00 29.14 O ATOM 1337 N ALA B 132 2.596 24.318 −21.183 1.00 27.61 NATOM 1338 CA ALA B 132 3.286 23.232 −21.881 1.00 26.94 C ATOM 1339 CBALA B 132 2.302 22.385 −22.757 1.00 24.90 C ATOM 1340 C ALA B 132 4.44323.733 −22.737 1.00 26.64 C ATOM 1341 O ALA B 132 4.454 24.875 −23.1931.00 26.99 O ATOM 1342 N ASN B 133 5.405 22.846 −22.933 1.00 27.01 NATOM 1343 CA ASN B 133 6.506 23.033 −23.898 1.00 27.23 C ATOM 1344 CBASN B 133 7.863 22.830 −23.177 1.00 28.41 C ATOM 1345 CG ASN B 133 8.21124.006 −22.255 1.00 30.04 C ATOM 1346 OD1 ASN B 133 7.344 24.721 −21.8061.00 31.04 O ATOM 1347 ND2 ASN B 133 9.489 24.210 −21.993 1.00 34.78 NATOM 1348 C ASN B 133 6.293 22.000 −25.026 1.00 27.01 C ATOM 1349 O ASNB 133 6.084 20.793 −24.784 1.00 25.65 O ATOM 1350 N PHE B 134 6.29522.469 −26.277 1.00 28.15 N ATOM 1351 CA PHE B 134 5.929 21.577 −27.3491.00 29.30 C ATOM 1352 CB PHE B 134 4.400 21.283 −27.328 1.00 30.21 CATOM 1353 CG PHE B 134 3.533 22.520 −27.414 1.00 32.57 C ATOM 1354 CD1PHE B 134 3.094 23.009 −28.647 1.00 33.22 C ATOM 1355 CE1 PHE B 1342.312 24.154 −28.704 1.00 32.79 C ATOM 1356 CZ PHE B 134 1.955 24.809−27.541 1.00 33.90 C ATOM 1357 CE2 PHE B 134 2.401 24.324 −26.305 1.0032.40 C ATOM 1358 CD2 PHE B 134 3.165 23.197 −26.257 1.00 31.50 C ATOM1359 C PHE B 134 6.329 22.201 −28.682 1.00 29.84 C ATOM 1360 O PHE B 1346.534 23.409 −28.792 1.00 30.16 O ATOM 1361 N SER B 135 6.419 21.375−29.710 1.00 31.15 N ATOM 1362 CA SER B 135 6.679 21.941 −31.053 1.0032.23 C ATOM 1363 CB SER B 135 7.628 21.052 −31.812 1.00 32.51 C ATOM1364 OG SER B 135 7.036 19.812 −32.002 1.00 33.57 O ATOM 1365 C SER B135 5.386 22.073 −31.827 1.00 33.12 C ATOM 1366 O SER B 135 4.420 21.371−31.537 1.00 31.51 O ATOM 1367 N VAL B 136 5.389 22.959 −32.839 1.0034.96 N ATOM 1368 CA VAL B 136 4.225 23.143 −33.685 1.00 36.92 C ATOM1369 CB VAL B 136 3.385 24.440 −33.371 1.00 37.96 C ATOM 1370 CG1 VAL B136 2.815 24.423 −31.922 1.00 37.33 C ATOM 1371 CG2 VAL B 136 4.18525.652 −33.544 1.00 38.33 C ATOM 1372 C VAL B 136 4.701 23.143 −35.1161.00 38.73 C ATOM 1373 O VAL B 136 5.834 23.563 −35.409 1.00 38.26 OATOM 1374 N ILE B 137 3.882 22.554 −35.969 1.00 40.79 N ATOM 1375 CA ILEB 137 4.031 22.698 −37.411 1.00 44.55 C ATOM 1376 CB ILE B 137 4.63321.429 −38.099 1.00 44.67 C ATOM 1377 CG1 ILE B 137 3.919 20.174 −37.6511.00 45.11 C ATOM 1378 CD1 ILE B 137 4.421 18.930 −38.328 1.00 49.18 CATOM 1379 CG2 ILE B 137 6.109 21.293 −37.822 1.00 47.14 C ATOM 1380 CILE B 137 2.633 22.973 −37.940 1.00 45.83 C ATOM 1381 O ILE B 137 1.65822.408 −37.420 1.00 46.23 O ATOM 1382 N PHE B 138 2.539 23.867 −38.9321.00 48.16 N ATOM 1383 CA PHE B 138 1.279 24.178 −39.629 1.00 50.06 CATOM 1384 CB PHE B 138 0.792 22.974 −40.474 1.00 51.11 C ATOM 1385 CGPHE B 138 1.852 22.411 −41.398 1.00 53.72 C ATOM 1386 CD1 PHE B 1382.183 21.054 −41.358 1.00 57.35 C ATOM 1387 CE1 PHE B 138 3.189 20.518−42.204 1.00 57.68 C ATOM 1388 CZ PHE B 138 3.865 21.353 −43.080 1.0055.86 C ATOM 1389 CE2 PHE B 138 3.545 22.720 −43.124 1.00 57.45 C ATOM1390 CD2 PHE B 138 2.543 23.242 −42.286 1.00 55.69 C ATOM 1391 C PHE B138 0.210 24.607 −38.630 1.00 50.34 C ATOM 1392 O PHE B 138 −0.92324.093 −38.663 1.00 50.82 O ATOM 1393 N ASP B 139 0.598 25.525 −37.7411.00 50.41 N ATOM 1394 CA ASP B 139 −0.252 26.037 −36.637 1.00 50.56 CATOM 1395 CB ASP B 139 −1.150 27.178 −37.125 1.00 52.14 C ATOM 1396 CGASP B 139 −0.371 28.481 −37.289 1.00 54.55 C ATOM 1397 OD1 ASP B 1390.301 28.897 −36.307 1.00 57.23 O ATOM 1398 OD2 ASP B 139 −0.409 29.066−38.398 0.50 56.46 O ATOM 1399 C ASP B 139 −1.004 25.031 −35.770 1.0049.51 C ATOM 1400 O ASP B 139 −2.110 25.289 −35.243 1.00 49.37 O ATOM1401 N ARG B 140 −0.355 23.891 −35.580 1.00 47.68 N ATOM 1402 CA ARG B140 −0.920 22.771 −34.875 1.00 46.64 C ATOM 1403 CB ARG B 140 −1.36121.736 −35.917 1.00 47.18 C ATOM 1404 CG ARG B 140 −1.906 20.430 −35.3651.00 50.69 C ATOM 1405 CD ARG B 140 −1.832 19.264 −36.415 1.00 52.62 CATOM 1406 NE ARG B 140 −0.462 19.002 −36.903 1.00 62.39 N ATOM 1407 CZARG B 140 0.398 18.184 −36.289 1.00 65.34 C ATOM 1408 NH1 ARG B 1400.013 17.558 −35.174 1.00 65.52 N ATOM 1409 NH2 ARG B 140 1.629 17.979−36.783 1.00 64.58 N ATOM 1410 C ARG B 140 0.174 22.207 −33.955 1.0043.25 C ATOM 1411 O ARG B 140 1.338 22.141 −34.342 1.00 41.78 O ATOM1412 N LEU B 141 −0.196 21.798 −32.742 1.00 40.18 N ATOM 1413 CA LEU B141 0.762 21.133 −31.854 1.00 38.38 C ATOM 1414 CB LEU B 141 0.16020.825 −30.457 1.00 37.77 C ATOM 1415 CG LEU B 141 1.045 20.010 −29.4741.00 36.52 C ATOM 1416 CD1 LEU B 141 0.754 20.416 −28.016 1.00 35.80 CATOM 1417 CD2 LEU B 141 0.821 18.523 −29.680 1.00 30.24 C ATOM 1418 CLEU B 141 1.214 19.859 −32.553 1.00 38.09 C ATOM 1419 O LEU B 141 0.38619.077 −33.023 1.00 37.31 O ATOM 1420 N GLU B 142 2.535 19.671 −32.6071.00 37.00 N ATOM 1421 CA GLU B 142 3.161 18.538 −33.253 1.00 36.10 CATOM 1422 CB GLU B 142 4.385 19.046 −34.050 1.00 36.59 C ATOM 1423 CGGLU B 142 5.078 17.967 −34.887 1.00 38.15 C ATOM 1424 CD GLU B 142 6.46418.401 −35.444 1.00 40.42 C ATOM 1425 OE1 GLU B 142 6.918 17.751 −36.4041.00 44.80 O ATOM 1426 OE2 GLU B 142 7.121 19.345 −34.931 1.00 44.67 OATOM 1427 C GLU B 142 3.586 17.478 −32.219 1.00 33.59 C ATOM 1428 O GLUB 142 3.102 16.346 −32.228 1.00 32.76 O ATOM 1429 N THR B 143 4.49617.869 −31.332 1.00 32.21 N ATOM 1430 CA THR B 143 5.113 16.979 −30.3341.00 30.26 C ATOM 1431 CB THR B 143 6.590 16.671 −30.699 1.00 30.51 CATOM 1432 OG1 THR B 143 6.584 15.914 −31.919 1.00 33.87 O ATOM 1433 CG2THR B 143 7.249 15.807 −29.661 1.00 27.91 C ATOM 1434 C THR B 143 5.09117.688 −28.988 1.00 28.93 C ATOM 1435 O THR B 143 5.617 18.800 −28.8521.00 30.12 O ATOM 1436 N LEU B 144 4.487 17.032 −28.002 1.00 27.73 NATOM 1437 CA LEU B 144 4.567 17.508 −26.616 1.00 26.43 C ATOM 1438 CBLEU B 144 3.431 16.875 −25.801 1.00 26.11 C ATOM 1439 CG LEU B 144 3.40317.233 −24.313 1.00 24.22 C ATOM 1440 CD1 LEU B 144 3.063 18.671 −24.1831.00 22.62 C ATOM 1441 CD2 LEU B 144 2.368 16.369 −23.592 1.00 25.40 CATOM 1442 C LEU B 144 5.925 17.128 −26.008 1.00 26.12 C ATOM 1443 O LEUB 144 6.324 15.957 −26.032 1.00 26.26 O ATOM 1444 N ILE B 145 6.59418.101 −25.407 1.00 26.39 N ATOM 1445 CA ILE B 145 7.767 17.789 −24.5741.00 27.56 C ATOM 1446 CB ILE B 145 8.807 18.976 −24.557 1.00 27.90 CATOM 1447 CG1 ILE B 145 9.241 19.389 −25.990 1.00 31.80 C ATOM 1448 CD1ILE B 145 9.501 18.216 −26.807 1.00 32.94 C ATOM 1449 CG2 ILE B 14510.021 18.674 −23.598 1.00 27.03 C ATOM 1450 C ILE B 145 7.278 17.493−23.132 1.00 26.46 C ATOM 1451 O ILE B 145 7.527 16.432 −22.576 1.0025.81 O ATOM 1452 N LEU B 146 6.530 18.428 −22.568 1.00 26.06 N ATOM1453 CA LEU B 146 6.041 18.267 −21.202 1.00 26.05 C ATOM 1454 CB LEU B146 7.173 18.571 −20.208 1.00 24.89 C ATOM 1455 CG LEU B 146 6.93118.388 −18.678 1.00 26.17 C ATOM 1456 CD1 LEU B 146 6.582 16.951 −18.3141.00 25.01 C ATOM 1457 CD2 LEU B 146 8.135 18.936 −17.871 1.00 27.73 CATOM 1458 C LEU B 146 4.890 19.191 −20.970 1.00 24.78 C ATOM 1459 O LEUB 146 4.935 20.345 −21.394 1.00 26.29 O ATOM 1460 N LEU B 147 3.86318.723 −20.243 1.00 24.66 N ATOM 1461 CA LEU B 147 2.797 19.643 −19.8561.00 23.39 C ATOM 1462 CB LEU B 147 1.441 19.193 −20.441 1.00 23.05 CATOM 1463 CG LEU B 147 0.225 20.095 −20.123 1.00 24.92 C ATOM 1464 CD1LEU B 147 −0.772 19.974 −21.269 1.00 24.09 C ATOM 1465 CD2 LEU B 147−0.444 19.655 −18.790 1.00 25.78 C ATOM 1466 C LEU B 147 2.752 19.524−18.346 1.00 23.23 C ATOM 1467 O LEU B 147 2.810 18.426 −17.860 1.0023.78 O ATOM 1468 N ARG B 148 2.610 20.634 −17.638 1.00 24.18 N ATOM1469 CA ARG B 148 2.443 20.592 −16.171 1.00 25.22 C ATOM 1470 CB ARG B148 3.744 20.991 −15.459 1.00 23.74 C ATOM 1471 CG ARG B 148 4.73119.806 −15.393 1.00 24.24 C ATOM 1472 CD ARG B 148 6.127 20.136 −14.7931.00 24.73 C ATOM 1473 NE ARG B 148 6.742 18.845 −14.478 1.00 26.57 NATOM 1474 CZ ARG B 148 7.951 18.685 −13.915 1.00 27.32 C ATOM 1475 NH1ARG B 148 8.675 19.731 −13.582 1.00 27.44 N ATOM 1476 NH2 ARG B 1488.397 17.473 −13.660 1.00 26.04 N ATOM 1477 C ARG B 148 1.327 21.521−15.719 1.00 25.27 C ATOM 1478 O ARG B 148 1.089 22.525 −16.348 1.0026.12 O ATOM 1479 N ALA B 149 0.732 21.216 −14.560 1.00 27.06 N ATOM1480 CA ALA B 149 −0.365 22.016 −14.035 1.00 26.93 C ATOM 1481 CB ALA B149 −1.557 21.094 −13.669 1.00 25.27 C ATOM 1482 C ALA B 149 0.14022.794 −12.817 1.00 27.42 C ATOM 1483 O ALA B 149 0.668 22.201 −11.8751.00 26.74 O ATOM 1484 N PHE B 150 −0.011 24.108 −12.845 1.00 28.46 NATOM 1485 CA PHE B 150 0.541 24.969 −11.779 1.00 31.48 C ATOM 1486 CBPHE B 150 1.476 26.039 −12.378 1.00 30.90 C ATOM 1487 CG PHE B 150 2.68325.461 −13.023 1.00 31.68 C ATOM 1488 CD1 PHE B 150 2.642 25.053 −14.3691.00 31.92 C ATOM 1489 CE1 PHE B 150 3.777 24.515 −14.992 1.00 31.87 CATOM 1490 CZ PHE B 150 4.963 24.346 −14.254 1.00 31.46 C ATOM 1491 CE2PHE B 150 4.996 24.724 −12.907 1.00 35.16 C ATOM 1492 CD2 PHE B 1503.864 25.283 −12.294 1.00 32.53 C ATOM 1493 C PHE B 150 −0.523 25.681−10.979 1.00 32.52 C ATOM 1494 O PHE B 150 −1.468 26.207 −11.536 1.0033.40 O ATOM 1495 N THR B 151 −0.344 25.709 −9.671 1.00 34.98 N ATOM1496 CA THR B 151 −1.181 26.568 −8.824 1.00 36.44 C ATOM 1497 CB THR B151 −1.101 26.201 −7.334 1.00 34.71 C ATOM 1498 OG1 THR B 151 0.20526.513 −6.846 1.00 34.94 O ATOM 1499 CG2 THR B 151 −1.306 24.732 −7.1671.00 35.77 C ATOM 1500 C THR B 151 −0.693 27.978 −8.994 1.00 38.85 CATOM 1501 O THR B 151 0.368 28.212 −9.580 1.00 38.32 O ATOM 1502 N GLU B152 −1.473 28.927 −8.484 1.00 42.00 N ATOM 1503 CA GLU B 152 −1.13930.341 −8.597 1.00 44.30 C ATOM 1504 CB GLU B 152 −2.230 31.168 −7.9511.00 45.82 C ATOM 1505 CG GLU B 152 −3.314 31.579 −8.878 1.00 48.98 CATOM 1506 CD GLU B 152 −4.434 32.252 −8.130 1.00 51.85 C ATOM 1507 OE1GLU B 152 −4.303 32.390 −6.903 1.00 52.93 O ATOM 1508 OE2 GLU B 152−5.445 32.619 −8.752 1.00 54.82 O ATOM 1509 C GLU B 152 0.186 30.680−7.952 1.00 44.72 C ATOM 1510 O GLU B 152 0.841 31.641 −8.347 1.00 45.93O ATOM 1511 N GLU B 153 0.567 29.881 −6.961 1.00 45.12 N ATOM 1512 CAGLU B 153 1.817 30.034 −6.242 1.00 45.17 C ATOM 1513 CB GLU B 153 1.66929.415 −4.855 1.00 46.29 C ATOM 1514 CG GLU B 153 0.191 29.411 −4.3461.00 51.61 C ATOM 1515 CD GLU B 153 −0.230 30.758 −3.760 1.00 58.99 CATOM 1516 OE1 GLU B 153 0.679 31.558 −3.403 1.00 61.45 O ATOM 1517 OE2GLU B 153 −1.462 31.023 −3.653 1.00 61.26 O ATOM 1518 C GLU B 153 2.97929.367 −6.992 1.00 44.04 C ATOM 1519 O GLU B 153 4.143 29.417 −6.5351.00 43.59 O ATOM 1520 N GLY B 154 2.675 28.728 −8.131 1.00 41.32 N ATOM1521 CA GLY B 154 3.724 28.130 −8.934 1.00 37.57 C ATOM 1522 C GLY B 1544.036 26.702 −8.539 1.00 36.03 C ATOM 1523 O GLY B 154 5.054 26.151−8.942 1.00 35.84 O ATOM 1524 N ALA B 155 3.182 26.072 −7.740 1.00 33.82N ATOM 1525 CA ALA B 155 3.465 24.653 −7.375 1.00 32.57 C ATOM 1526 CBALA B 155 2.925 24.332 −6.013 1.00 32.09 C ATOM 1527 C ALA B 155 2.86523.701 −8.439 1.00 31.21 C ATOM 1528 O ALA B 155 1.803 24.000 −8.9871.00 32.00 O ATOM 1529 N ILE B 156 3.544 22.579 −8.704 1.00 30.83 N ATOM1530 CA ILE B 156 3.093 21.593 −9.732 1.00 29.85 C ATOM 1531 CB ILE B156 4.257 20.837 −10.408 1.00 29.30 C ATOM 1532 CG1 ILE B 156 5.18521.822 −11.123 1.00 30.27 C ATOM 1533 CD1 ILE B 156 6.673 21.342 −11.2571.00 24.87 C ATOM 1534 CG2 ILE B 156 3.732 19.766 −11.402 1.00 30.34 CATOM 1535 C ILE B 156 2.168 20.588 −9.094 1.00 29.67 C ATOM 1536 O ILE B156 2.477 20.002 −8.031 1.00 28.50 O ATOM 1537 N VAL B 157 0.999 20.401−9.710 1.00 28.52 N ATOM 1538 CA VAL B 157 0.035 19.457 −9.155 1.0029.03 C ATOM 1539 CB VAL B 157 −1.210 20.203 −8.605 1.00 28.67 C ATOM1540 CG1 VAL B 157 −0.805 21.289 −7.551 1.00 29.30 C ATOM 1541 CG2 VAL B157 −2.015 20.844 −9.723 1.00 28.06 C ATOM 1542 C VAL B 157 −0.39518.326 −10.108 1.00 28.97 C ATOM 1543 O VAL B 157 −1.082 17.409 −9.6841.00 29.30 O ATOM 1544 N GLY B 158 0.037 18.405 −11.383 1.00 28.12 NATOM 1545 CA GLY B 158 −0.251 17.387 −12.380 1.00 27.35 C ATOM 1546 CGLY B 158 0.715 17.552 −13.554 1.00 26.84 C ATOM 1547 O GLY B 158 1.29718.625 −13.730 1.00 25.99 O ATOM 1548 N GLU B 159 0.931 16.466 −14.2901.00 27.11 N ATOM 1549 CA GLU B 159 1.705 16.564 −15.543 1.00 28.08 CATOM 1550 CB GLU B 159 3.218 16.605 −15.275 1.00 27.46 C ATOM 1551 CGGLU B 159 3.852 15.305 −15.222 1.00 30.14 C ATOM 1552 CD GLU B 159 5.36115.328 −14.806 1.00 30.39 C ATOM 1553 OE1 GLU B 159 5.908 14.231 −14.8221.00 33.34 O ATOM 1554 OE2 GLU B 159 5.948 16.375 −14.425 1.00 32.04 OATOM 1555 C GLU B 159 1.361 15.466 −16.559 1.00 27.20 C ATOM 1556 O GLUB 159 0.757 14.462 −16.226 1.00 27.15 O ATOM 1557 N ILE B 160 1.69415.741 −17.823 1.00 27.13 N ATOM 1558 CA ILE B 160 1.587 14.755 −18.8831.00 27.82 C ATOM 1559 CB ILE B 160 0.478 15.135 −19.891 1.00 28.16 CATOM 1560 CG1 ILE B 160 −0.874 15.160 −19.168 1.00 26.78 C ATOM 1561 CD1ILE B 160 −1.939 15.991 −19.916 1.00 27.37 C ATOM 1562 CG2 ILE B 1600.390 14.107 −21.028 1.00 26.30 C ATOM 1563 C ILE B 160 2.983 14.739−19.516 1.00 27.85 C ATOM 1564 O ILE B 160 3.518 15.785 −19.859 1.0026.40 O ATOM 1565 N SER B 161 3.589 13.569 −19.559 1.00 28.39 N ATOM1566 CA SER B 161 4.891 13.446 −20.194 1.00 30.42 C ATOM 1567 CB SER B161 6.019 13.335 −19.158 1.00 29.53 C ATOM 1568 OG SER B 161 5.70512.327 −18.230 1.00 36.43 O ATOM 1569 C SER B 161 4.891 12.216 −21.0921.00 30.22 C ATOM 1570 O SER B 161 4.212 11.225 −20.815 1.00 29.26 OATOM 1571 N PRO B 162 5.653 12.292 −22.198 1.00 31.73 N ATOM 1572 CA PROB 162 5.830 11.168 −23.108 1.00 33.40 C ATOM 1573 CB PRO B 162 6.62011.787 −24.278 1.00 33.86 C ATOM 1574 CG PRO B 162 6.244 13.258 −24.2151.00 34.21 C ATOM 1575 CD PRO B 162 6.298 13.505 −22.706 1.00 31.95 CATOM 1576 C PRO B 162 6.604 10.061 −22.459 1.00 34.81 C ATOM 1577 O PROB 162 7.528 10.343 −21.712 1.00 35.86 O ATOM 1578 N LEU B 163 6.2028.819 −22.718 1.00 36.44 N ATOM 1579 CA LEU B 163 6.904 7.630 −22.2501.00 40.34 C ATOM 1580 CB LEU B 163 5.974 6.431 −22.203 1.00 40.13 CATOM 1581 CG LEU B 163 4.712 6.559 −21.340 1.00 42.63 C ATOM 1582 CD1LEU B 163 3.831 5.395 −21.657 1.00 43.88 C ATOM 1583 CD2 LEU B 163 5.1336.493 −19.879 1.00 46.62 C ATOM 1584 C LEU B 163 8.064 7.304 −23.2021.00 42.84 C ATOM 1585 O LEU B 163 7.864 7.201 −24.420 1.00 42.13 O ATOM1586 N PRO B 164 9.269 7.100 −22.634 1.00 45.85 N ATOM 1587 CA PRO B 16410.548 6.943 −23.375 1.00 47.72 C ATOM 1588 CB PRO B 164 11.519 6.449−22.297 1.00 47.76 C ATOM 1589 CG PRO B 164 10.921 6.900 −21.004 1.0048.29 C ATOM 1590 CD PRO B 164 9.429 6.889 −21.184 1.00 45.64 C ATOM1591 C PRO B 164 10.428 5.855 −24.422 1.00 49.11 C ATOM 1592 O PRO B 16410.863 6.022 −25.593 1.00 50.40 O ATOM 1593 N SER B 165 9.806 4.760−23.985 1.00 50.00 N ATOM 1594 CA SER B 165 9.705 3.526 −24.738 1.0050.56 C ATOM 1595 CB SER B 165 9.385 2.399 −23.779 1.00 50.90 C ATOM1596 OG SER B 165 8.001 2.416 −23.479 1.00 51.74 O ATOM 1597 C SER B 1658.651 3.547 −25.847 1.00 50.55 C ATOM 1598 O SER B 165 8.291 2.493−26.384 1.00 51.11 O ATOM 1599 N PHE B 166 8.129 4.720 −26.188 1.0049.55 N ATOM 1600 CA PHE B 166 7.297 4.812 −27.372 1.00 48.18 C ATOM1601 CB PHE B 166 5.913 5.364 −27.074 1.00 48.72 C ATOM 1602 CG PHE B166 4.950 4.328 −26.515 1.00 50.30 C ATOM 1603 CD1 PHE B 166 3.954 3.777−27.318 1.00 52.19 C ATOM 1604 CE1 PHE B 166 3.045 2.834 −26.811 1.0053.48 C ATOM 1605 CZ PHE B 166 3.139 2.431 −25.480 1.00 52.84 C ATOM1606 CE2 PHE B 166 4.123 2.993 −24.657 1.00 51.29 C ATOM 1607 CD2 PHE B166 5.020 3.928 −25.178 1.00 51.96 C ATOM 1608 C PHE B 166 8.029 5.623−28.425 1.00 47.26 C ATOM 1609 O PHE B 166 8.808 6.516 −28.089 1.0046.10 O ATOM 1610 N PRO B 167 7.814 5.284 −29.715 1.00 46.43 N ATOM 1611CA PRO B 167 8.561 6.016 −30.748 1.00 45.41 C ATOM 1612 CB PRO B 1678.412 5.128 −31.984 1.00 45.90 C ATOM 1613 CG PRO B 167 7.006 4.463−31.803 1.00 46.91 C ATOM 1614 CD PRO B 167 6.894 4.265 −30.275 1.0045.94 C ATOM 1615 C PRO B 167 7.970 7.416 −30.995 1.00 44.77 C ATOM 1616O PRO B 167 8.647 8.278 −31.586 1.00 45.20 O ATOM 1617 N GLY B 168 6.7297.654 −30.545 1.00 42.28 N ATOM 1618 CA GLY B 168 6.100 8.961 −30.7621.00 38.80 C ATOM 1619 C GLY B 168 4.652 9.017 −30.289 1.00 36.63 C ATOM1620 O GLY B 168 4.144 8.066 −29.741 1.00 35.45 O ATOM 1621 N HIS B 1693.998 10.148 −30.497 1.00 35.02 N ATOM 1622 CA HIS B 169 2.574 10.257−30.146 1.00 34.10 C ATOM 1623 CB HIS B 169 2.430 10.713 −28.678 1.0032.49 C ATOM 1624 CG HIS B 169 3.112 12.018 −28.401 1.00 30.56 C ATOM1625 ND1 HIS B 169 4.370 12.092 −27.835 1.00 28.47 N ATOM 1626 CE1 HIS B169 4.745 13.365 −27.779 1.00 27.07 C ATOM 1627 NE2 HIS B 169 3.75814.116 −28.244 1.00 26.23 N ATOM 1628 CD2 HIS B 169 2.735 13.298 −28.6561.00 26.61 C ATOM 1629 C HIS B 169 1.995 11.315 −31.050 1.00 33.97 CATOM 1630 O HIS B 169 2.737 12.034 −31.732 1.00 34.14 O ATOM 1631 N THRB 170 0.672 11.472 −31.016 1.00 33.87 N ATOM 1632 CA THR B 170 0.03212.498 −31.835 1.00 34.49 C ATOM 1633 CB THR B 170 −0.951 11.856 −32.8411.00 35.29 C ATOM 1634 OG1 THR B 170 −2.138 11.488 −32.134 1.00 38.23 OATOM 1635 CG2 THR B 170 −0.340 10.570 −33.492 1.00 34.81 C ATOM 1636 CTHR B 170 −0.744 13.511 −30.985 1.00 33.67 C ATOM 1637 O THR B 170−0.985 13.293 −29.780 1.00 32.49 O ATOM 1638 N ILE B 171 −1.123 14.609−31.616 1.00 32.84 N ATOM 1639 CA ILE B 171 −2.019 15.577 −30.986 1.0033.37 C ATOM 1640 CB ILE B 171 −2.458 16.719 −31.968 1.00 33.99 C ATOM1641 CG1 ILE B 171 −3.157 17.840 −31.181 1.00 33.44 C ATOM 1642 CD1 ILEB 171 −3.493 19.085 −31.943 1.00 32.95 C ATOM 1643 CG2 ILE B 171 −3.32016.164 −33.168 1.00 34.46 C ATOM 1644 C ILE B 171 −3.248 14.895 −30.3791.00 32.88 C ATOM 1645 O ILE B 171 −3.825 15.377 −29.383 1.00 32.45 OATOM 1646 N GLU B 172 −3.673 13.775 −30.957 1.00 32.23 N ATOM 1647 CAGLU B 172 −4.881 13.160 −30.431 1.00 32.31 C ATOM 1648 CB GLU B 172−5.553 12.253 −31.434 1.00 33.12 C ATOM 1649 CG GLU B 172 −5.931 12.970−32.772 1.00 38.08 C ATOM 1650 CD GLU B 172 −7.034 14.096 −32.699 1.0042.24 C ATOM 1651 OE1 GLU B 172 −7.962 14.120 −31.828 1.00 38.52 O ATOM1652 OE2 GLU B 172 −6.976 14.957 −33.605 1.00 44.85 O ATOM 1653 C GLU B172 −4.575 12.439 −29.117 1.00 31.00 C ATOM 1654 O GLU B 172 −5.42712.354 −28.221 1.00 29.39 O ATOM 1655 N ASP B 173 −3.364 11.925 −28.9941.00 29.29 N ATOM 1656 CA ASP B 173 −2.957 11.312 −27.728 1.00 28.81 CATOM 1657 CB ASP B 173 −1.597 10.654 −27.827 1.00 28.63 C ATOM 1658 CGASP B 173 −1.591 9.462 −28.738 1.00 30.62 C ATOM 1659 OD1 ASP B 173−2.461 8.581 −28.601 1.00 29.41 O ATOM 1660 OD2 ASP B 173 −0.660 9.403−29.549 1.00 33.78 O ATOM 1661 C ASP B 173 −2.880 12.394 −26.684 1.0027.22 C ATOM 1662 O ASP B 173 −3.223 12.156 −25.524 1.00 29.09 O ATOM1663 N VAL B 174 −2.390 13.553 −27.090 1.00 26.94 N ATOM 1664 CA VAL B174 −2.212 14.683 −26.195 1.00 27.05 C ATOM 1665 CB VAL B 174 −1.43115.823 −26.851 1.00 27.03 C ATOM 1666 CG1 VAL B 174 −1.453 17.050−25.954 1.00 27.31 C ATOM 1667 CG2 VAL B 174 0.046 15.419 −27.117 1.0028.19 C ATOM 1668 C VAL B 174 −3.594 15.143 −25.715 1.00 27.12 C ATOM1669 O VAL B 174 −3.845 15.343 −24.519 1.00 24.96 O ATOM 1670 N LYS B175 −4.523 15.267 −26.650 1.00 25.83 N ATOM 1671 CA LYS B 175 −5.87415.649 −26.236 1.00 26.01 C ATOM 1672 CB LYS B 175 −6.749 15.904 −27.4581.00 26.17 C ATOM 1673 CG LYS B 175 −6.739 17.324 −27.834 1.00 30.35 CATOM 1674 CD LYS B 175 −6.102 17.480 −29.128 1.00 38.18 C ATOM 1675 CELYS B 175 −7.142 17.623 −30.145 1.00 37.08 C ATOM 1676 NZ LYS B 175−7.550 19.051 −30.104 1.00 42.61 N ATOM 1677 C LYS B 175 −6.542 14.661−25.292 1.00 25.19 C ATOM 1678 O LYS B 175 −7.220 15.074 −24.345 1.0026.66 O ATOM 1679 N ASN B 176 −6.414 13.358 −25.543 1.00 23.95 N ATOM1680 CA ASN B 176 −6.974 12.363 −24.636 1.00 23.14 C ATOM 1681 CB ASN B176 −6.557 10.938 −25.058 1.00 24.94 C ATOM 1682 CG ASN B 176 −7.20610.470 −26.375 1.00 26.18 C ATOM 1683 OD1 ASN B 176 −8.233 11.005−26.802 1.00 29.88 O ATOM 1684 ND2 ASN B 176 −6.606 9.452 −26.994 1.0029.47 N ATOM 1685 C ASN B 176 −6.446 12.572 −23.184 1.00 23.69 C ATOM1686 O ASN B 176 −7.234 12.592 −22.206 1.00 22.87 O ATOM 1687 N ALA B177 −5.119 12.682 −23.064 1.00 22.91 N ATOM 1688 CA ALA B 177 −4.44212.879 −21.767 1.00 23.94 C ATOM 1689 CB ALA B 177 −2.902 12.772 −21.9241.00 25.51 C ATOM 1690 C ALA B 177 −4.806 14.179 −21.085 1.00 22.98 CATOM 1691 O ALA B 177 −4.986 14.189 −19.863 1.00 23.61 O ATOM 1692 N ILEB 178 −4.923 15.267 −21.832 1.00 23.01 N ATOM 1693 CA ILE B 178 −5.39116.554 −21.279 1.00 24.94 C ATOM 1694 CB ILE B 178 −5.277 17.726 −22.3151.00 23.97 C ATOM 1695 CG1 ILE B 178 −3.783 18.066 −22.574 1.00 25.98 CATOM 1696 CD1 ILE B 178 −3.585 19.202 −23.573 1.00 27.04 C ATOM 1697 CG2ILE B 178 −5.957 18.997 −21.792 1.00 24.69 C ATOM 1698 C ILE B 178−6.823 16.495 −20.696 1.00 25.65 C ATOM 1699 O ILE B 178 −7.076 16.967−19.583 1.00 26.20 O ATOM 1700 N GLY B 179 −7.741 15.872 −21.421 1.0024.86 N ATOM 1701 CA GLY B 179 −9.067 15.626 −20.868 1.00 25.64 C ATOM1702 C GLY B 179 −9.022 14.827 −19.572 1.00 26.53 C ATOM 1703 O GLY B179 −9.759 15.131 −18.648 1.00 27.05 O ATOM 1704 N VAL B 180 −8.18113.778 −19.488 1.00 27.64 N ATOM 1705 CA VAL B 180 −8.096 12.989 −18.2301.00 26.49 C ATOM 1706 CB VAL B 180 −7.242 11.709 −18.330 1.00 27.34 CATOM 1707 CG1 VAL B 180 −6.987 11.099 −16.920 1.00 27.00 C ATOM 1708 CG2VAL B 180 −7.918 10.674 −19.251 1.00 26.03 C ATOM 1709 C VAL B 180−7.571 13.854 −17.088 1.00 26.25 C ATOM 1710 O VAL B 180 −8.148 13.836−15.964 1.00 26.42 O ATOM 1711 N LEU B 181 −6.511 14.607 −17.353 1.0025.79 N ATOM 1712 CA LEU B 181 −5.949 15.522 −16.345 1.00 26.04 C ATOM1713 CB LEU B 181 −4.587 16.119 −16.807 1.00 26.20 C ATOM 1714 CG LEU B181 −3.936 17.200 −15.923 1.00 26.41 C ATOM 1715 CD1 LEU B 181 −3.51716.667 −14.581 1.00 22.34 C ATOM 1716 CD2 LEU B 181 −2.717 17.769−16.620 1.00 24.16 C ATOM 1717 C LEU B 181 −6.890 16.637 −15.881 1.0026.68 C ATOM 1718 O LEU B 181 −7.083 16.841 −14.654 1.00 26.04 O ATOM1719 N ILE B 182 −7.471 17.363 −16.835 1.00 26.09 N ATOM 1720 CA ILE B182 −8.388 18.436 −16.532 1.00 25.74 C ATOM 1721 CB ILE B 182 −8.86119.141 −17.805 1.00 26.51 C ATOM 1722 CG1 ILE B 182 −7.723 19.973−18.396 1.00 24.82 C ATOM 1723 CD1 ILE B 182 −8.143 20.834 −19.674 1.0025.81 C ATOM 1724 CG2 ILE B 182 −10.124 20.002 −17.515 1.00 27.97 C ATOM1725 C ILE B 182 −9.608 17.916 −15.775 1.00 26.63 C ATOM 1726 O ILE B182 −10.110 18.623 −14.867 1.00 26.56 O ATOM 1727 N GLY B 183 −10.08416.717 −16.143 1.00 25.84 N ATOM 1728 CA GLY B 183 −11.280 16.150−15.538 1.00 26.48 C ATOM 1729 C GLY B 183 −10.999 15.788 −14.062 1.0026.93 C ATOM 1730 O GLY B 183 −11.881 15.926 −13.212 1.00 25.70 O ATOM1731 N GLY B 184 −9.780 15.311 −13.765 1.00 24.71 N ATOM 1732 CA GLY B184 −9.412 14.978 −12.383 1.00 27.81 C ATOM 1733 C GLY B 184 −9.31716.235 −11.536 1.00 27.95 C ATOM 1734 O GLY B 184 −9.831 16.263 −10.4111.00 29.12 O ATOM 1735 N LEU B 185 −8.698 17.278 −12.075 1.00 27.43 NATOM 1736 CA LEU B 185 −8.556 18.574 −11.373 1.00 26.86 C ATOM 1737 CBLEU B 185 −7.718 19.529 −12.199 1.00 26.76 C ATOM 1738 CG LEU B 185−6.203 19.174 −12.300 1.00 25.88 C ATOM 1739 CD1 LEU B 185 −5.629 20.023−13.351 1.00 24.14 C ATOM 1740 CD2 LEU B 185 −5.470 19.340 −10.922 1.0024.41 C ATOM 1741 C LEU B 185 −9.938 19.230 −11.118 1.00 28.13 C ATOM1742 O LEU B 185 −10.205 19.698 −10.025 1.00 27.27 O ATOM 1743 N GLU B186 −10.779 19.302 −12.148 1.00 26.45 N ATOM 1744 CA GLU B 186 −12.17619.722 −12.017 1.00 28.86 C ATOM 1745 CB GLU B 186 −12.913 19.596−13.378 1.00 28.42 C ATOM 1746 CG GLU B 186 −12.605 20.641 −14.405 1.0031.60 C ATOM 1747 CD GLU B 186 −13.303 20.308 −15.787 1.00 33.01 C ATOM1748 OE1 GLU B 186 −13.747 19.131 −16.049 1.00 34.53 O ATOM 1749 OE2 GLUB 186 −13.393 21.253 −16.571 1.00 35.62 O ATOM 1750 C GLU B 186 −12.91818.895 −10.986 1.00 28.14 C ATOM 1751 O GLU B 186 −13.594 19.470 −10.1521.00 29.83 O ATOM 1752 N TRP B 187 −12.839 17.557 −11.049 1.00 27.79 NATOM 1753 CA TRP B 187 −13.520 16.713 −10.106 1.00 29.99 C ATOM 1754 CBTRP B 187 −13.187 15.237 −10.335 1.00 30.68 C ATOM 1755 CG TRP B 187−13.585 14.307 −9.227 1.00 34.71 C ATOM 1756 CD1 TRP B 187 −12.79413.848 −8.167 1.00 35.56 C ATOM 1757 NE1 TRP B 187 −13.496 12.989 −7.3731.00 36.67 N ATOM 1758 CE2 TRP B 187 −14.761 12.866 −7.899 1.00 38.56 CATOM 1759 CD2 TRP B 187 −14.847 13.686 −9.060 1.00 35.87 C ATOM 1760 CE3TRP B 187 −16.049 13.746 −9.774 1.00 34.89 C ATOM 1761 CZ3 TRP B 187−17.098 13.013 −9.333 1.00 37.19 C ATOM 1762 CH2 TRP B 187 −16.99812.205 −8.162 1.00 37.23 C ATOM 1763 CZ2 TRP B 187 −15.835 12.128 −7.4351.00 38.41 C ATOM 1764 C TRP B 187 −13.187 17.105 −8.646 1.00 29.34 CATOM 1765 O TRP B 187 −14.051 16.999 −7.782 1.00 26.13 O ATOM 1766 N ASNB 188 −11.933 17.528 −8.418 1.00 29.25 N ATOM 1767 CA ASN B 188 −11.42618.015 −7.112 1.00 30.10 C ATOM 1768 CB ASN B 188 −9.922 17.678 −6.9601.00 30.98 C ATOM 1769 CG ASN B 188 −9.691 16.346 −6.270 1.00 28.83 CATOM 1770 OD1 ASN B 188 −10.634 15.706 −5.865 1.00 30.25 O ATOM 1771 ND2ASN B 188 −8.427 15.909 −6.166 1.00 27.24 N ATOM 1772 C ASN B 188−11.645 19.483 −6.856 1.00 30.32 C ATOM 1773 O ASN B 188 −10.987 20.074−6.005 1.00 31.38 O ATOM 1774 N ASP B 189 −12.578 20.083 −7.576 1.0031.64 N ATOM 1775 CA ASP B 189 −12.989 21.492 −7.404 1.00 31.66 C ATOM1776 CB ASP B 189 −13.739 21.693 −6.056 1.00 33.12 C ATOM 1777 CG ASP B189 −15.040 20.898 −6.016 1.00 37.29 C ATOM 1778 OD1 ASP B 189 −15.82521.100 −6.970 1.00 38.57 O ATOM 1779 OD2 ASP B 189 −15.261 20.060 −5.0841.00 40.54 O ATOM 1780 C ASP B 189 −11.916 22.524 −7.602 1.00 32.43 CATOM 1781 O ASP B 189 −11.978 23.619 −7.028 1.00 30.55 O ATOM 1782 N ASNB 190 −10.930 22.197 −8.443 1.00 30.63 N ATOM 1783 CA ASN B 190 −10.00123.204 −8.912 1.00 30.98 C ATOM 1784 CB ASN B 190 −8.642 22.559 −9.2441.00 29.41 C ATOM 1785 CG ASN B 190 −8.039 21.837 −8.058 1.00 27.80 CATOM 1786 OD1 ASN B 190 −7.559 22.467 −7.100 1.00 28.21 O ATOM 1787 ND2ASN B 190 −8.069 20.507 −8.096 1.00 24.72 N ATOM 1788 C ASN B 190−10.590 23.894 −10.133 1.00 31.62 C ATOM 1789 O ASN B 190 −11.320 23.270−10.893 1.00 31.86 O ATOM 1790 N THR B 191 −10.304 25.184 −10.298 1.0032.87 N ATOM 1791 CA THR B 191 −10.634 25.916 −11.509 1.00 34.75 C ATOM1792 CB THR B 191 −10.945 27.380 −11.169 1.00 35.55 C ATOM 1793 OG1 THRB 191 −12.062 27.415 −10.261 1.00 37.47 O ATOM 1794 CG2 THR B 191−11.328 28.148 −12.411 1.00 37.42 C ATOM 1795 C THR B 191 −9.437 25.837−12.451 1.00 34.83 C ATOM 1796 O THR B 191 −8.304 26.214 −12.070 1.0035.55 O ATOM 1797 N VAL B 192 −9.681 25.329 −13.661 1.00 34.58 N ATOM1798 CA VAL B 192 −8.604 25.019 −14.605 1.00 34.33 C ATOM 1799 CB VAL B192 −8.616 23.526 −15.076 1.00 33.53 C ATOM 1800 CG1 VAL B 192 −7.38723.231 −16.021 1.00 34.55 C ATOM 1801 CG2 VAL B 192 −8.565 22.595−13.908 1.00 31.05 C ATOM 1802 C VAL B 192 −8.607 25.959 −15.788 1.0035.32 C ATOM 1803 O VAL B 192 −9.593 26.041 −16.515 1.00 35.56 O ATOM1804 N ARG B 193 −7.495 26.665 −15.987 1.00 35.84 N ATOM 1805 CA ARG B193 −7.252 27.415 −17.216 1.00 37.58 C ATOM 1806 CB ARG B 193 −6.86828.876 −16.900 1.00 37.82 C ATOM 1807 CG ARG B 193 −8.073 29.733 −16.5431.00 42.79 C ATOM 1808 CD ARG B 193 −7.707 31.011 −15.825 1.00 50.50 CATOM 1809 NE ARG B 193 −8.639 31.231 −14.712 1.00 55.68 N ATOM 1810 CZARG B 193 −8.545 30.633 −13.517 1.00 58.91 C ATOM 1811 NH1 ARG B 193−7.546 29.763 −13.241 1.00 59.58 N ATOM 1812 NH2 ARG B 193 −9.454 30.908−12.589 1.00 59.65 N ATOM 1813 C ARG B 193 −6.111 26.775 −18.010 1.0037.54 C ATOM 1814 O ARG B 193 −5.287 26.058 −17.449 1.00 36.53 O ATOM1815 N VAL B 194 −6.055 27.093 −19.306 1.00 37.96 N ATOM 1816 CA VAL B194 −5.076 26.501 −20.232 1.00 37.55 C ATOM 1817 CB VAL B 194 −5.83425.611 −21.268 1.00 38.83 C ATOM 1818 CG1 VAL B 194 −5.025 25.322−22.493 1.00 40.07 C ATOM 1819 CG2 VAL B 194 −6.213 24.302 −20.615 1.0035.70 C ATOM 1820 C VAL B 194 −4.301 27.662 −20.840 1.00 37.68 C ATOM1821 O VAL B 194 −4.886 28.739 −21.085 1.00 36.58 O ATOM 1822 N SER B195 −2.984 27.496 −21.020 1.00 36.31 N ATOM 1823 CA SER B 195 −2.17128.555 −21.584 1.00 35.49 C ATOM 1824 CB SER B 195 −0.710 28.091 −21.7101.00 35.57 C ATOM 1825 OG SER B 195 −0.564 27.142 −22.752 1.00 33.21 OATOM 1826 C SER B 195 −2.770 28.982 −22.950 1.00 36.06 C ATOM 1827 O SERB 195 −3.429 28.171 −23.634 1.00 34.56 O ATOM 1828 N LYS B 196 −2.59730.252 −23.306 1.00 36.20 N ATOM 1829 CA LYS B 196 −3.116 30.760 −24.5761.00 37.88 C ATOM 1830 CB LYS B 196 −2.919 32.264 −24.713 1.00 38.69 CATOM 1831 CG LYS B 196 −3.804 33.084 −23.759 1.00 43.56 C ATOM 1832 CDLYS B 196 −3.659 34.583 −24.100 1.00 49.67 C ATOM 1833 CE LYS B 196−4.059 35.504 −22.919 1.00 52.45 C ATOM 1834 NZ LYS B 196 −2.985 35.632−21.851 1.00 53.35 N ATOM 1835 C LYS B 196 −2.448 30.060 −25.745 1.0037.09 C ATOM 1836 O LYS B 196 −3.068 29.898 −26.784 1.00 37.20 O ATOM1837 N THR B 197 −1.189 29.652 −25.576 1.00 36.42 N ATOM 1838 CA THR B197 −0.530 28.848 −26.612 1.00 36.69 C ATOM 1839 CB THR B 197 0.99228.707 −26.426 1.00 36.21 C ATOM 1840 OG1 THR B 197 1.260 28.069 −25.1621.00 38.36 O ATOM 1841 CG2 THR B 197 1.678 30.046 −26.531 1.00 38.13 CATOM 1842 C THR B 197 −1.122 27.451 −26.718 1.00 35.35 C ATOM 1843 O THRB 197 −1.297 26.953 −27.793 1.00 35.92 O ATOM 1844 N LEU B 198 −1.41826.809 −25.601 1.00 36.53 N ATOM 1845 CA LEU B 198 −2.068 25.516 −25.6571.00 36.92 C ATOM 1846 CB LEU B 198 −2.180 24.876 −24.275 1.00 36.99 CATOM 1847 CG LEU B 198 −1.098 23.952 −23.729 1.00 33.23 C ATOM 1848 CD1LEU B 198 −1.449 23.661 −22.274 1.00 33.04 C ATOM 1849 CD2 LEU B 198−1.072 22.672 −24.603 1.00 29.08 C ATOM 1850 C LEU B 198 −3.467 25.655−26.256 1.00 39.11 C ATOM 1851 O LEU B 198 −3.850 24.850 −27.092 1.0038.44 O ATOM 1852 N GLN B 199 −4.252 26.646 −25.830 1.00 41.80 N ATOM1853 CA GLN B 199 −5.572 26.806 −26.478 1.00 45.46 C ATOM 1854 CB GLN B199 −6.537 27.763 −25.752 1.00 45.75 C ATOM 1855 CG GLN B 199 −6.00829.085 −25.299 1.00 49.36 C ATOM 1856 CD GLN B 199 −6.963 29.806 −24.2951.00 50.29 C ATOM 1857 OE1 GLN B 199 −7.702 29.163 −23.540 1.00 54.54 OATOM 1858 NE2 GLN B 199 −6.935 31.148 −24.303 1.00 55.26 N ATOM 1859 CGLN B 199 −5.467 27.120 −27.970 1.00 45.02 C ATOM 1860 O GLN B 199−6.285 26.660 −28.731 1.00 45.85 O ATOM 1861 N ARG B 200 −4.444 27.854−28.388 1.00 45.93 N ATOM 1862 CA ARG B 200 −4.258 28.142 −29.827 1.0047.16 C ATOM 1863 CB ARG B 200 −3.270 29.269 −30.062 1.00 47.37 C ATOM1864 CG ARG B 200 −2.927 29.415 −31.545 1.00 50.46 C ATOM 1865 CD ARG B200 −2.055 30.607 −31.841 1.00 54.16 C ATOM 1866 NE ARG B 200 −1.83130.736 −33.284 1.00 58.36 N ATOM 1867 CZ ARG B 200 −0.821 31.406 −33.8531.00 60.38 C ATOM 1868 NH1 ARG B 200 0.099 32.036 −33.117 1.00 59.70 NATOM 1869 NH2 ARG B 200 −0.728 31.438 −35.178 1.00 61.24 N ATOM 1870 CARG B 200 −3.823 26.940 −30.663 1.00 47.23 C ATOM 1871 O ARG B 200−4.319 26.733 −31.775 1.00 47.03 O ATOM 1872 N PHE B 201 −2.886 26.162−30.134 1.00 47.51 N ATOM 1873 CA PHE B 201 −2.210 25.130 −30.932 1.0047.97 C ATOM 1874 CB PHE B 201 −0.697 25.178 −30.715 1.00 46.65 C ATOM1875 CG PHE B 201 −0.060 26.428 −31.243 1.00 46.30 C ATOM 1876 CD1 PHE B201 −0.158 26.752 −32.596 1.00 46.65 C ATOM 1877 CE1 PHE B 201 0.42627.888 −33.096 1.00 44.92 C ATOM 1878 CZ PHE B 201 1.120 28.730 −32.2441.00 48.15 C ATOM 1879 CE2 PHE B 201 1.217 28.419 −30.878 1.00 46.43 CATOM 1880 CD2 PHE B 201 0.632 27.280 −30.399 1.00 44.50 C ATOM 1881 CPHE B 201 −2.753 23.736 −30.726 1.00 48.74 C ATOM 1882 O PHE B 201−2.597 22.864 −31.593 1.00 48.64 O ATOM 1883 N ALA B 202 −3.370 23.508−29.576 1.00 50.44 N ATOM 1884 CA ALA B 202 −4.033 22.247 −29.341 1.0053.42 C ATOM 1885 CB ALA B 202 −3.728 21.709 −27.948 1.00 52.66 C ATOM1886 C ALA B 202 −5.543 22.370 −29.606 1.00 54.73 C ATOM 1887 O ALA B202 −6.238 21.374 −29.502 1.00 56.24 O ATOM 1888 N TRP B 203 −6.01123.586 −29.956 1.00 56.29 N ATOM 1889 CA TRP B 203 −7.395 23.933 −30.4551.00 56.94 C ATOM 1890 CB TRP B 203 −8.380 24.142 −29.301 1.00 58.23 CATOM 1891 CG TRP B 203 −8.552 22.939 −28.504 1.00 59.56 C ATOM 1892 CD1TRP B 203 −9.345 21.864 −28.804 1.00 61.53 C ATOM 1893 NE1 TRP B 203−9.230 20.906 −27.822 1.00 62.77 N ATOM 1894 CE2 TRP B 203 −8.340 21.347−26.873 1.00 62.01 C ATOM 1895 CD2 TRP B 203 −7.901 22.632 −27.269 1.0061.50 C ATOM 1896 CE3 TRP B 203 −6.983 23.310 −26.460 1.00 62.77 C ATOM1897 CZ3 TRP B 203 −6.547 22.698 −25.292 1.00 61.79 C ATOM 1898 CH2 TRPB 203 −7.013 21.418 −24.918 1.00 61.03 C ATOM 1899 CZ2 TRP B 203 −7.89820.730 −25.690 1.00 60.64 C ATOM 1900 C TRP B 203 −7.437 25.187 −31.3661.00 57.77 C ATOM 1901 O TRP B 203 −8.201 26.147 −31.186 1.00 57.76 OATOM 1902 OXT TRP B 203 −6.692 25.319 −32.339 1.00 58.42 O ATOM 1903 NHIS D 56 34.592 2.339 9.216 1.00 64.66 N ATOM 1904 CA HIS D 56 34.3452.715 10.649 1.00 64.55 C ATOM 1905 CB HIS D 56 35.029 1.705 11.625 1.0065.47 C ATOM 1906 CG HIS D 56 36.531 1.764 11.637 1.00 68.06 C ATOM 1907ND1 HIS D 56 37.317 1.022 10.777 1.00 71.84 N ATOM 1908 CE1 HIS D 5638.593 1.276 11.018 1.00 72.28 C ATOM 1909 NE2 HIS D 56 38.664 2.15412.006 1.00 70.72 N ATOM 1910 CD2 HIS D 56 37.390 2.469 12.415 1.0069.56 C ATOM 1911 C HIS D 56 34.649 4.212 10.979 1.00 63.35 C ATOM 1912O HIS D 56 35.235 4.560 12.024 1.00 63.93 O ATOM 1913 N HIS D 57 34.2125.104 10.095 1.00 61.01 N ATOM 1914 CA HIS D 57 34.497 6.533 10.244 1.0058.95 C ATOM 1915 CB HIS D 57 35.769 6.906 9.444 1.00 59.82 C ATOM 1916CG HIS D 57 36.783 5.797 9.346 1.00 62.98 C ATOM 1917 ND1 HIS D 5736.602 4.683 8.545 1.00 66.61 N ATOM 1918 CE1 HIS D 57 37.641 3.8728.672 1.00 67.08 C ATOM 1919 NE2 HIS D 57 38.490 4.417 9.528 1.00 67.51N ATOM 1920 CD2 HIS D 57 37.979 5.622 9.961 1.00 66.43 C ATOM 1921 C HISD 57 33.300 7.267 9.654 1.00 55.91 C ATOM 1922 O HIS D 57 32.887 6.9318.536 1.00 56.18 O ATOM 1923 N HIS D 58 32.694 8.230 10.355 1.00 51.42 NATOM 1924 CA HIS D 58 31.740 9.014 9.589 1.00 47.26 C ATOM 1925 CB HIS D58 30.404 9.340 10.238 1.00 48.71 C ATOM 1926 CG HIS D 58 29.369 9.5969.188 1.00 54.11 C ATOM 1927 ND1 HIS D 58 28.703 10.793 9.049 1.00 58.72N ATOM 1928 CE1 HIS D 58 27.920 10.740 7.977 1.00 61.41 C ATOM 1929 NE2HIS D 58 28.103 9.573 7.379 1.00 60.54 N ATOM 1930 CD2 HIS D 58 29.0098.842 8.112 1.00 59.27 C ATOM 1931 C HIS D 58 32.286 10.247 8.894 1.0042.65 C ATOM 1932 O HIS D 58 33.093 10.973 9.453 1.00 40.85 O ATOM 1933N HIS D 59 31.787 10.482 7.680 1.00 37.62 N ATOM 1934 CA HIS D 59 32.12011.671 6.915 1.00 33.38 C ATOM 1935 CB HIS D 59 31.913 11.451 5.408 1.0031.80 C ATOM 1936 CG HIS D 59 32.889 10.495 4.815 1.00 30.00 C ATOM 1937ND1 HIS D 59 34.093 10.904 4.271 1.00 26.51 N ATOM 1938 CE1 HIS D 5934.761 9.837 3.865 1.00 28.12 C ATOM 1939 NE2 HIS D 59 34.015 8.7654.067 1.00 27.17 N ATOM 1940 CD2 HIS D 59 32.845 9.148 4.679 1.00 28.48C ATOM 1941 C HIS D 59 31.362 12.894 7.336 1.00 32.02 C ATOM 1942 O HISD 59 31.849 13.970 7.117 1.00 32.51 O ATOM 1943 N MET D 60 30.150 12.7657.885 1.00 31.80 N ATOM 1944 CA MET D 60 29.369 13.977 8.243 1.00 31.40C ATOM 1945 CB MET D 60 27.889 13.902 7.828 1.00 32.22 C ATOM 1946 CGMET D 60 27.617 13.875 6.267 1.00 37.88 C ATOM 1947 SD MET D 60 27.80815.376 5.183 1.00 44.72 S ATOM 1948 CE MET D 60 26.475 16.498 5.654 1.0045.45 C ATOM 1949 C MET D 60 29.501 14.277 9.760 1.00 29.90 C ATOM 1950O MET D 60 29.577 13.361 10.575 1.00 28.64 O ATOM 1951 N SER D 61 29.53515.557 10.109 1.00 30.29 N ATOM 1952 CA SER D 61 29.588 15.983 11.4991.00 30.76 C ATOM 1953 CB SER D 61 29.925 17.460 11.570 1.00 30.74 CATOM 1954 OG SER D 61 28.848 18.250 11.070 1.00 29.96 O ATOM 1955 C SERD 61 28.253 15.750 12.221 1.00 32.49 C ATOM 1956 O SER D 61 28.20615.601 13.460 1.00 32.22 O ATOM 1957 N GLY D 62 27.173 15.744 11.4521.00 33.25 N ATOM 1958 CA GLY D 62 25.831 15.442 11.967 1.00 34.91 CATOM 1959 C GLY D 62 24.939 15.316 10.728 1.00 37.02 C ATOM 1960 O GLY D62 25.415 15.463 9.602 1.00 36.12 O ATOM 1961 N GLU D 63 23.649 15.05610.903 1.00 38.27 N ATOM 1962 CA GLU D 63 22.778 15.047 9.723 1.00 41.05C ATOM 1963 CB GLU D 63 22.745 13.647 9.064 1.00 41.25 C ATOM 1964 CGGLU D 63 21.929 12.590 9.806 1.00 44.88 C ATOM 1965 CD GLU D 63 22.09211.175 9.212 1.00 45.68 C ATOM 1966 OE1 GLU D 63 21.509 10.883 8.1301.00 50.03 O ATOM 1967 OE2 GLU D 63 22.789 10.347 9.848 1.00 51.89 OATOM 1968 C GLU D 63 21.359 15.560 10.053 1.00 40.41 C ATOM 1969 O GLU D63 20.917 15.481 11.203 1.00 39.58 O ATOM 1970 N LYS D 64 20.675 16.0799.030 1.00 39.97 N ATOM 1971 CA LYS D 64 19.253 16.453 9.124 1.00 39.55C ATOM 1972 CB LYS D 64 18.855 17.312 7.933 1.00 38.27 C ATOM 1973 CGLYS D 64 19.498 18.676 7.978 1.00 37.25 C ATOM 1974 CD LYS D 64 19.35219.392 6.699 1.00 37.42 C ATOM 1975 CE LYS D 64 19.582 20.874 6.890 1.0040.00 C ATOM 1976 NZ LYS D 64 19.659 21.591 5.597 1.00 41.12 N ATOM 1977C LYS D 64 18.447 15.173 9.226 1.00 39.27 C ATOM 1978 O LYS D 64 18.59814.260 8.428 1.00 40.43 O ATOM 1979 N THR D 65 17.612 15.062 10.241 1.0040.07 N ATOM 1980 CA THR D 65 17.000 13.756 10.492 1.00 40.21 C ATOM1981 CB THR D 65 17.075 13.371 11.988 1.00 40.76 C ATOM 1982 OG1 THR D65 16.660 14.502 12.769 1.00 42.99 O ATOM 1983 CG2 THR D 65 18.53212.999 12.379 1.00 42.94 C ATOM 1984 C THR D 65 15.543 13.715 10.0261.00 38.61 C ATOM 1985 O THR D 65 14.950 12.653 9.998 1.00 38.55 O ATOM1986 N VAL D 66 14.976 14.875 9.685 1.00 37.32 N ATOM 1987 CA VAL D 6613.577 14.945 9.213 1.00 36.16 C ATOM 1988 CB VAL D 66 12.658 15.60710.304 1.00 37.17 C ATOM 1989 CG1 VAL D 66 11.174 15.588 9.875 1.0036.22 C ATOM 1990 CG2 VAL D 66 12.797 14.868 11.625 1.00 37.85 C ATOM1991 C VAL D 66 13.414 15.723 7.913 1.00 34.38 C ATOM 1992 O VAL D 6613.926 16.848 7.791 1.00 33.99 O ATOM 1993 N VAL D 67 12.646 15.1596.969 1.00 34.25 N ATOM 1994 CA VAL D 67 12.330 15.843 5.687 1.00 33.06C ATOM 1995 CB VAL D 67 11.704 14.865 4.636 1.00 33.93 C ATOM 1996 CG1VAL D 67 11.168 15.648 3.370 1.00 30.51 C ATOM 1997 CG2 VAL D 67 12.69113.730 4.262 1.00 34.10 C ATOM 1998 C VAL D 67 11.411 17.069 5.921 1.0032.76 C ATOM 1999 O VAL D 67 10.519 17.011 6.756 1.00 33.03 O ATOM 2000N CYS D 68 11.676 18.179 5.236 1.00 32.16 N ATOM 2001 CA CYS D 68 10.90719.397 5.407 1.00 32.44 C ATOM 2002 CB CYS D 68 11.597 20.575 4.774 1.0031.82 C ATOM 2003 SG CYS D 68 10.774 22.098 5.030 1.00 33.61 S ATOM 2004C CYS D 68 9.550 19.203 4.723 1.00 32.88 C ATOM 2005 O CYS D 68 9.47619.154 3.491 1.00 30.62 O ATOM 2006 N LYS D 69 8.484 19.090 5.519 1.0033.15 N ATOM 2007 CA LYS D 69 7.172 18.858 4.910 1.00 34.88 C ATOM 2008CB LYS D 69 6.157 18.270 5.917 1.00 35.34 C ATOM 2009 CG LYS D 69 5.81119.205 7.044 1.00 36.65 C ATOM 2010 CD LYS D 69 4.712 18.618 7.967 1.0037.03 C ATOM 2011 CE LYS D 69 3.257 18.968 7.480 1.00 37.27 C ATOM 2012NZ LYS D 69 2.907 20.446 7.579 1.00 36.89 N ATOM 2013 C LYS D 69 6.67620.095 4.180 1.00 35.15 C ATOM 2014 O LYS D 69 5.946 19.975 3.181 1.0035.27 O ATOM 2015 N HIS D 70 7.104 21.288 4.605 1.00 37.08 N ATOM 2016CA HIS D 70 6.813 22.498 3.813 1.00 38.20 C ATOM 2017 CB HIS D 70 7.19523.768 4.561 1.00 39.21 C ATOM 2018 CG HIS D 70 6.402 23.956 5.819 1.0043.73 C ATOM 2019 ND1 HIS D 70 6.986 24.109 7.059 1.00 46.35 N ATOM 2020CE1 HIS D 70 6.045 24.214 7.979 1.00 47.53 C ATOM 2021 NE2 HIS D 704.869 24.094 7.387 1.00 49.18 N ATOM 2022 CD2 HIS D 70 5.063 23.9406.035 1.00 46.48 C ATOM 2023 C HIS D 70 7.467 22.438 2.441 1.00 38.73 CATOM 2024 O HIS D 70 6.829 22.759 1.422 1.00 39.48 O ATOM 2025 N TRP D71 8.725 21.994 2.397 1.00 38.01 N ATOM 2026 CA TRP D 71 9.446 21.8871.121 1.00 36.93 C ATOM 2027 CB TRP D 71 10.920 21.482 1.360 1.00 36.60C ATOM 2028 CG TRP D 71 11.596 21.051 0.116 1.00 35.32 C ATOM 2029 CD1TRP D 71 12.129 21.868 −0.845 1.00 36.20 C ATOM 2030 NE1 TRP D 71 12.66621.117 −1.863 1.00 33.00 N ATOM 2031 CE2 TRP D 71 12.492 19.786 −1.5751.00 33.99 C ATOM 2032 CD2 TRP D 71 11.801 19.706 −0.337 1.00 33.26 CATOM 2033 CE3 TRP D 71 11.486 18.448 0.185 1.00 29.61 C ATOM 2034 CZ3TRP D 71 11.830 17.336 −0.535 1.00 34.23 C ATOM 2035 CH2 TRP D 71 12.49817.450 −1.790 1.00 34.83 C ATOM 2036 CZ2 TRP D 71 12.820 18.668 −2.3191.00 32.77 C ATOM 2037 C TRP D 71 8.754 20.885 0.194 1.00 37.16 C ATOM2038 O TRP D 71 8.694 21.086 −1.021 1.00 37.02 O ATOM 2039 N LEU D 728.255 19.790 0.744 1.00 37.29 N ATOM 2040 CA LEU D 72 7.503 18.834−0.072 1.00 38.20 C ATOM 2041 CB LEU D 72 6.952 17.721 0.795 1.00 37.67C ATOM 2042 CG LEU D 72 7.960 16.753 1.405 1.00 38.01 C ATOM 2043 CD1LEU D 72 7.214 15.930 2.418 1.00 36.10 C ATOM 2044 CD2 LEU D 72 8.55415.878 0.336 1.00 37.04 C ATOM 2045 C LEU D 72 6.381 19.501 −0.894 1.0038.76 C ATOM 2046 O LEU D 72 6.122 19.104 −2.037 1.00 38.00 O ATOM 2047N ARG D 73 5.789 20.555 −0.332 1.00 39.92 N ATOM 2048 CA ARG D 73 4.60821.205 −0.903 1.00 41.93 C ATOM 2049 CB ARG D 73 3.477 21.262 0.139 1.0041.43 C ATOM 2050 CG ARG D 73 3.054 19.908 0.710 1.00 41.64 C ATOM 2051CD ARG D 73 1.665 20.001 1.435 1.00 42.77 C ATOM 2052 NE ARG D 73 0.57720.306 0.489 1.00 41.40 N ATOM 2053 CZ ARG D 73 −0.128 21.435 0.432 1.0041.05 C ATOM 2054 NH1 ARG D 73 0.061 22.426 1.297 1.00 38.28 N ATOM 2055NH2 ARG D 73 −1.048 21.575 −0.533 1.00 40.79 N ATOM 2056 C ARG D 734.926 22.597 −1.457 1.00 43.33 C ATOM 2057 O ARG D 73 4.018 23.377−1.768 1.00 44.11 O ATOM 2058 N GLY D 74 6.222 22.914 −1.564 1.00 44.01N ATOM 2059 CA GLY D 74 6.686 24.181 −2.145 1.00 45.02 C ATOM 2060 C GLYD 74 6.470 25.382 −1.248 1.00 45.92 C ATOM 2061 O GLY D 74 6.309 26.515−1.713 1.00 46.72 O ATOM 2062 N LEU D 75 6.445 25.149 0.051 1.00 46.34 NATOM 2063 CA LEU D 75 6.107 26.222 0.997 1.00 47.13 C ATOM 2064 CB LEU D75 4.934 25.777 1.885 1.00 46.90 C ATOM 2065 CG LEU D 75 3.568 25.6691.231 1.00 46.99 C ATOM 2066 CD1 LEU D 75 2.730 24.757 2.056 1.00 48.19C ATOM 2067 CD2 LEU D 75 2.944 27.049 1.136 1.00 47.54 C ATOM 2068 C LEUD 75 7.309 26.631 1.869 1.00 47.52 C ATOM 2069 O LEU D 75 7.141 27.2452.939 1.00 48.30 O ATOM 2070 N CYS D 76 8.509 26.251 1.423 1.00 47.15 NATOM 2071 CA CYS D 76 9.741 26.554 2.151 1.00 47.29 C ATOM 2072 CB CYS D76 10.341 25.307 2.803 1.00 46.82 C ATOM 2073 SG CYS D 76 11.782 25.6643.833 1.00 44.67 S ATOM 2074 C CYS D 76 10.736 27.187 1.201 1.00 47.45 CATOM 2075 O CYS D 76 11.029 26.650 0.125 1.00 47.30 O ATOM 2076 N LYS D77 11.231 28.342 1.639 1.00 48.56 N ATOM 2077 CA LYS D 77 12.129 29.2180.883 1.00 49.52 C ATOM 2078 CB LYS D 77 11.691 30.695 1.055 1.00 50.19C ATOM 2079 CG LYS D 77 10.278 31.028 0.538 1.00 53.97 C ATOM 2080 CDLYS D 77 10.225 30.845 −0.981 1.00 58.79 C ATOM 2081 CE LYS D 77 9.05029.979 −1.397 1.00 62.13 C ATOM 2082 NZ LYS D 77 9.133 29.643 −2.8581.00 64.34 N ATOM 2083 C LYS D 77 13.584 29.101 1.377 1.00 48.54 C ATOM2084 O LYS D 77 14.485 29.711 0.788 1.00 48.99 O ATOM 2085 N LYS D 7813.787 28.351 2.466 1.00 47.21 N ATOM 2086 CA LYS D 78 15.080 28.2693.165 1.00 46.17 C ATOM 2087 CB LYS D 78 14.865 27.778 4.588 1.00 45.59C ATOM 2088 CG LYS D 78 14.052 28.736 5.431 1.00 48.72 C ATOM 2089 CDLYS D 78 13.535 28.042 6.657 1.00 51.08 C ATOM 2090 CE LYS D 78 12.62628.955 7.426 1.00 54.63 C ATOM 2091 NZ LYS D 78 12.237 28.258 8.680 1.0057.29 N ATOM 2092 C LYS D 78 16.216 27.465 2.488 1.00 45.04 C ATOM 2093O LYS D 78 17.366 27.532 2.929 1.00 45.07 O ATOM 2094 N GLY D 79 15.91226.718 1.432 1.00 43.75 N ATOM 2095 CA GLY D 79 16.935 25.956 0.712 1.0042.63 C ATOM 2096 C GLY D 79 17.814 25.108 1.629 1.00 41.82 C ATOM 2097O GLY D 79 17.323 24.490 2.582 1.00 41.57 O ATOM 2098 N ASP D 80 19.11825.104 1.346 1.00 41.32 N ATOM 2099 CA ASP D 80 20.137 24.381 2.150 1.0041.34 C ATOM 2100 CB ASP D 80 21.551 24.566 1.548 1.00 40.65 C ATOM 2101CG ASP D 80 21.723 23.844 0.223 1.00 41.10 C ATOM 2102 OD1 ASP D 8020.833 23.048 −0.171 1.00 41.81 O ATOM 2103 OD2 ASP D 80 22.763 24.061−0.440 1.00 41.86 O ATOM 2104 C ASP D 80 20.153 24.779 3.609 1.00 40.66C ATOM 2105 O ASP D 80 20.533 23.985 4.474 1.00 40.51 O ATOM 2106 N GLND 81 19.678 25.988 3.874 1.00 40.84 N ATOM 2107 CA GLN D 81 19.72826.572 5.205 1.00 40.62 C ATOM 2108 CB GLN D 81 19.909 28.096 5.119 1.0040.77 C ATOM 2109 CG GLN D 81 21.305 28.536 4.655 1.00 41.97 C ATOM 2110CD GLN D 81 21.538 28.288 3.171 1.00 43.96 C ATOM 2111 OE1 GLN D 8120.627 28.463 2.370 1.00 44.29 O ATOM 2112 NE2 GLN D 81 22.752 27.8782.797 1.00 40.50 N ATOM 2113 C GLN D 81 18.514 26.200 6.071 1.00 40.22 CATOM 2114 O GLN D 81 18.448 26.615 7.231 1.00 39.54 O ATOM 2115 N CYS D82 17.575 25.410 5.526 1.00 39.25 N ATOM 2116 CA CYS D 82 16.459 24.9236.329 1.00 38.42 C ATOM 2117 CB CYS D 82 15.385 24.223 5.486 1.00 38.37C ATOM 2118 SG CYS D 82 13.883 23.896 6.491 1.00 38.87 S ATOM 2119 C CYSD 82 16.962 23.975 7.411 1.00 38.75 C ATOM 2120 O CYS D 82 17.970 23.2967.235 1.00 38.23 O ATOM 2121 N GLU D 83 16.260 23.945 8.534 1.00 38.22 NATOM 2122 CA GLU D 83 16.586 23.050 9.622 1.00 38.64 C ATOM 2123 CB GLUD 83 15.717 23.407 10.845 1.00 38.85 C ATOM 2124 CG GLU D 83 15.73822.391 11.960 1.00 39.99 C ATOM 2125 CD GLU D 83 14.765 22.732 13.1111.00 43.45 C ATOM 2126 OE1 GLU D 83 14.146 23.834 13.100 1.00 49.61 OATOM 2127 OE2 GLU D 83 14.624 21.882 14.025 1.00 47.89 O ATOM 2128 C GLUD 83 16.364 21.615 9.174 1.00 36.61 C ATOM 2129 O GLU D 83 16.969 20.6639.694 1.00 36.20 O ATOM 2130 N PHE D 84 15.448 21.458 8.218 1.00 35.98 NATOM 2131 CA PHE D 84 14.988 20.138 7.797 1.00 33.86 C ATOM 2132 CB PHED 84 13.445 20.073 7.860 1.00 34.81 C ATOM 2133 CG PHE D 84 12.90820.343 9.227 1.00 34.72 C ATOM 2134 CD1 PHE D 84 12.327 21.562 9.5221.00 37.93 C ATOM 2135 CE1 PHE D 84 11.841 21.806 10.805 1.00 39.57 CATOM 2136 CZ PHE D 84 11.981 20.835 11.803 1.00 37.48 C ATOM 2137 CE2PHE D 84 12.557 19.631 11.533 1.00 39.44 C ATOM 2138 CD2 PHE D 84 13.04319.389 10.238 1.00 37.62 C ATOM 2139 C PHE D 84 15.488 19.841 6.394 1.0032.86 C ATOM 2140 O PHE D 84 15.867 20.728 5.679 1.00 31.87 O ATOM 2141N LEU D 85 15.452 18.576 6.012 1.00 32.17 N ATOM 2142 CA LEU D 85 16.09018.146 4.793 1.00 32.87 C ATOM 2143 CB LEU D 85 16.309 16.646 4.887 1.0032.14 C ATOM 2144 CG LEU D 85 16.987 15.995 3.686 1.00 32.65 C ATOM 2145CD1 LEU D 85 18.475 16.518 3.562 1.00 30.51 C ATOM 2146 CD2 LEU D 8516.905 14.484 3.898 1.00 32.51 C ATOM 2147 C LEU D 85 15.234 18.4443.563 1.00 34.15 C ATOM 2148 O LEU D 85 14.022 18.140 3.554 1.00 33.04 OATOM 2149 N HIS D 86 15.865 19.006 2.527 1.00 33.66 N ATOM 2150 CA HIS D86 15.177 19.238 1.282 1.00 34.81 C ATOM 2151 CB HIS D 86 15.456 20.6390.786 1.00 34.31 C ATOM 2152 CG HIS D 86 14.760 21.691 1.587 1.00 33.56C ATOM 2153 ND1 HIS D 86 14.431 22.914 1.062 1.00 35.34 N ATOM 2154 CE1HIS D 86 13.867 23.653 1.998 1.00 35.36 C ATOM 2155 NE2 HIS D 86 13.76122.928 3.092 1.00 34.33 N ATOM 2156 CD2 HIS D 86 14.323 21.700 2.8691.00 32.93 C ATOM 2157 C HIS D 86 15.424 18.223 0.195 1.00 35.48 C ATOM2158 O HIS D 86 15.701 18.615 −0.934 1.00 36.99 O ATOM 2159 N GLU D 8715.339 16.938 0.533 1.00 36.60 N ATOM 2160 CA GLU D 87 15.300 15.870−0.461 1.00 38.04 C ATOM 2161 CB GLU D 87 16.656 15.148 −0.598 1.0038.88 C ATOM 2162 CG GLU D 87 17.818 16.031 −1.075 1.00 41.12 C ATOM2163 CD GLU D 87 17.624 16.634 −2.476 1.00 45.48 C ATOM 2164 OE1 GLU D87 16.697 16.215 −3.226 1.00 41.76 O ATOM 2165 OE2 GLU D 87 18.39917.568 −2.803 1.00 45.80 O ATOM 2166 C GLU D 87 14.230 14.862 −0.0821.00 38.87 C ATOM 2167 O GLU D 87 13.856 14.750 1.096 1.00 37.77 O ATOM2168 N TYR D 88 13.722 14.118 −1.058 1.00 40.40 N ATOM 2169 CA TYR D 8812.747 13.090 −0.695 1.00 42.60 C ATOM 2170 CB TYR D 88 11.639 12.789−1.767 1.00 43.58 C ATOM 2171 CG TYR D 88 10.558 11.877 −1.139 1.0046.74 C ATOM 2172 CD1 TYR D 88 9.714 12.348 −0.109 1.00 47.35 C ATOM2173 CE1 TYR D 88 8.769 11.503 0.523 1.00 49.00 C ATOM 2174 CZ TYR D 888.663 10.177 0.152 1.00 47.77 C ATOM 2175 OH TYR D 88 7.779 9.314 0.7841.00 47.83 O ATOM 2176 CE2 TYR D 88 9.506 9.679 −0.843 1.00 51.26 C ATOM2177 CD2 TYR D 88 10.460 10.530 −1.482 1.00 49.05 C ATOM 2178 C TYR D 8813.410 11.825 −0.149 1.00 42.69 C ATOM 2179 O TYR D 88 13.821 10.941−0.900 1.00 43.66 O ATOM 2180 N ASP D 89 13.461 11.710 1.169 1.00 42.43N ATOM 2181 CA ASP D 89 13.906 10.477 1.777 1.00 42.60 C ATOM 2182 CBASP D 89 15.119 10.778 2.648 1.00 42.36 C ATOM 2183 CG ASP D 89 15.7719.540 3.182 1.00 42.78 C ATOM 2184 OD1 ASP D 89 15.168 8.442 3.116 1.0042.68 O ATOM 2185 OD2 ASP D 89 16.914 9.667 3.670 1.00 44.94 O ATOM 2186C ASP D 89 12.776 9.836 2.595 1.00 43.43 C ATOM 2187 O ASP D 89 12.47610.292 3.696 1.00 42.72 O ATOM 2188 N MET D 90 12.179 8.762 2.069 1.0044.28 N ATOM 2189 CA MET D 90 10.995 8.143 2.686 1.00 47.28 C ATOM 2190CB MET D 90 10.397 7.019 1.805 1.00 46.57 C ATOM 2191 CG MET D 90 11.2725.745 1.686 1.00 50.99 C ATOM 2192 SD MET D 90 10.600 4.293 0.770 1.0055.26 S ATOM 2193 CE MET D 90 10.460 4.964 −0.896 1.00 54.61 C ATOM 2194C MET D 90 11.283 7.639 4.105 1.00 46.07 C ATOM 2195 O MET D 90 10.3557.302 4.848 1.00 45.61 O ATOM 2196 N THR D 91 12.570 7.594 4.466 1.0044.61 N ATOM 2197 CA THR D 91 12.987 7.061 5.747 1.00 43.51 C ATOM 2198CB THR D 91 14.350 6.254 5.648 1.00 44.59 C ATOM 2199 OG1 THR D 9115.463 7.160 5.457 1.00 45.89 O ATOM 2200 CG2 THR D 91 14.305 5.2014.517 1.00 44.25 C ATOM 2201 C THR D 91 13.144 8.164 6.764 1.00 41.77 CATOM 2202 O THR D 91 13.354 7.894 7.948 1.00 42.02 O ATOM 2203 N LYS D92 13.073 9.406 6.306 1.00 38.80 N ATOM 2204 CA LYS D 92 13.220 10.5397.197 1.00 37.66 C ATOM 2205 CB LYS D 92 14.428 11.401 6.773 1.00 37.27C ATOM 2206 CG LYS D 92 15.767 10.664 6.901 1.00 40.93 C ATOM 2207 CDLYS D 92 16.930 11.547 6.425 1.00 37.83 C ATOM 2208 CE LYS D 92 18.24510.765 6.528 1.00 45.63 C ATOM 2209 NZ LYS D 92 19.377 11.764 6.464 1.0044.22 N ATOM 2210 C LYS D 92 11.955 11.412 7.290 1.00 35.80 C ATOM 2211O LYS D 92 12.035 12.615 7.539 1.00 34.91 O ATOM 2212 N MET D 93 10.79210.805 7.099 1.00 34.90 N ATOM 2213 CA MET D 93 9.547 11.588 7.032 1.0033.48 C ATOM 2214 CB MET D 93 8.496 10.843 6.180 1.00 33.76 C ATOM 2215CG MET D 93 8.850 10.843 4.652 1.00 29.06 C ATOM 2216 SD MET D 93 8.66212.469 3.962 1.00 28.76 S ATOM 2217 CE MET D 93 6.963 12.472 3.449 1.0036.37 C ATOM 2218 C MET D 93 9.058 11.939 8.444 1.00 33.59 C ATOM 2219 OMET D 93 9.258 11.123 9.349 1.00 32.16 O ATOM 2220 N PRO D 94 8.46213.153 8.632 1.00 33.50 N ATOM 2221 CA PRO D 94 7.834 13.556 9.940 1.0034.10 C ATOM 2222 CB PRO D 94 7.201 14.957 9.670 1.00 32.63 C ATOM 2223CG PRO D 94 7.882 15.485 8.457 1.00 37.71 C ATOM 2224 CD PRO D 94 8.38014.248 7.607 1.00 35.59 C ATOM 2225 C PRO D 94 6.729 12.581 10.396 1.0033.49 C ATOM 2226 O PRO D 94 6.261 11.740 9.592 1.00 32.95 O ATOM 2227 NGLU D 95 6.306 12.700 11.664 1.00 31.40 N ATOM 2228 CA GLU D 95 5.26211.838 12.153 1.00 30.11 C ATOM 2229 CB GLU D 95 5.248 11.771 13.7041.00 31.59 C ATOM 2230 CG GLU D 95 4.077 10.906 14.222 1.00 31.29 C ATOM2231 CD GLU D 95 4.067 10.647 15.747 1.00 35.15 C ATOM 2232 OE1 GLU D 953.312 9.736 16.195 1.00 42.96 O ATOM 2233 OE2 GLU D 95 4.774 11.36716.469 1.00 42.80 O ATOM 2234 C GLU D 95 3.932 12.424 11.620 1.00 27.97C ATOM 2235 O GLU D 95 3.754 13.630 11.549 1.00 26.66 O ATOM 2236 N CYSD 96 3.012 11.552 11.271 1.00 27.21 N ATOM 2237 CA CYS D 96 1.677 11.98010.816 1.00 26.91 C ATOM 2238 CB CYS D 96 0.972 10.808 10.196 1.00 25.79C ATOM 2239 SG CYS D 96 −0.756 11.121 9.525 1.00 25.47 S ATOM 2240 C CYSD 96 0.833 12.538 11.964 1.00 27.38 C ATOM 2241 O CYS D 96 0.514 11.83712.909 1.00 27.92 O ATOM 2242 N TYR D 97 0.452 13.801 11.856 1.00 27.76N ATOM 2243 CA TYR D 97 −0.365 14.433 12.897 1.00 27.92 C ATOM 2244 CBTYR D 97 −0.652 15.878 12.528 1.00 28.47 C ATOM 2245 CG TYR D 97 −1.35416.646 13.643 1.00 29.52 C ATOM 2246 CD1 TYR D 97 −0.612 17.386 14.5601.00 30.25 C ATOM 2247 CE1 TYR D 97 −1.252 18.093 15.628 1.00 32.82 CATOM 2248 CZ TYR D 97 −2.655 18.015 15.752 1.00 30.54 C ATOM 2249 OH TYRD 97 −3.281 18.703 16.791 1.00 30.45 O ATOM 2250 CE2 TYR D 97 −3.41617.260 14.837 1.00 29.38 C ATOM 2251 CD2 TYR D 97 −2.766 16.571 13.8001.00 29.06 C ATOM 2252 C TYR D 97 −1.658 13.672 13.141 1.00 28.09 C ATOM2253 O TYR D 97 −2.045 13.435 14.298 1.00 27.25 O ATOM 2254 N PHE D 98−2.318 13.251 12.054 1.00 28.03 N ATOM 2255 CA PHE D 98 −3.631 12.61312.195 1.00 26.18 C ATOM 2256 CB PHE D 98 −4.407 12.608 10.863 1.0027.78 C ATOM 2257 CG PHE D 98 −4.754 14.003 10.412 1.00 25.25 C ATOM2258 CD1 PHE D 98 −5.815 14.669 10.990 1.00 25.95 C ATOM 2259 CE1 PHE D98 −6.092 15.991 10.625 1.00 25.50 C ATOM 2260 CZ PHE D 98 −5.302 16.6499.701 1.00 28.69 C ATOM 2261 CE2 PHE D 98 −4.223 16.002 9.144 1.00 31.29C ATOM 2262 CD2 PHE D 98 −3.963 14.666 9.492 1.00 27.25 C ATOM 2263 CPHE D 98 −3.515 11.238 12.812 1.00 28.26 C ATOM 2264 O PHE D 98 −4.31310.893 13.689 1.00 26.63 O ATOM 2265 N TYR D 99 −2.538 10.431 12.3751.00 28.21 N ATOM 2266 CA TYR D 99 −2.406 9.132 13.024 1.00 30.03 C ATOM2267 CB TYR D 99 −1.371 8.282 12.328 1.00 29.69 C ATOM 2268 CG TYR D 99−1.522 6.820 12.659 1.00 31.63 C ATOM 2269 CD1 TYR D 99 −2.409 6.01511.954 1.00 31.51 C ATOM 2270 CE1 TYR D 99 −2.547 4.671 12.258 1.0031.48 C ATOM 2271 CZ TYR D 99 −1.802 4.118 13.295 1.00 34.31 C ATOM 2272OH TYR D 99 −1.944 2.761 13.594 1.00 35.60 O ATOM 2273 CE2 TYR D 99−0.911 4.897 14.014 1.00 34.34 C ATOM 2274 CD2 TYR D 99 −0.772 6.23913.706 1.00 33.06 C ATOM 2275 C TYR D 99 −2.050 9.285 14.524 1.00 30.74C ATOM 2276 O TYR D 99 −2.528 8.521 15.362 1.00 31.10 O ATOM 2277 N SERD 100 −1.252 10.292 14.843 1.00 31.22 N ATOM 2278 CA SER D 100 −0.80810.499 16.231 1.00 33.97 C ATOM 2279 CB SER D 100 0.374 11.452 16.2811.00 33.74 C ATOM 2280 OG SER D 100 0.531 11.965 17.613 1.00 40.80 OATOM 2281 C SER D 100 −1.937 11.009 17.142 1.00 33.35 C ATOM 2282 O SERD 100 −2.116 10.476 18.259 1.00 34.24 O ATOM 2283 N LYS D 101 −2.66912.036 16.694 1.00 32.17 N ATOM 2284 CA LYS D 101 −3.748 12.598 17.5131.00 32.18 C ATOM 2285 CB LYS D 101 −4.019 14.090 17.233 1.00 31.57 CATOM 2286 CG LYS D 101 −2.787 14.947 17.229 1.00 35.32 C ATOM 2287 CDLYS D 101 −2.122 15.074 18.568 1.00 41.14 C ATOM 2288 CE LYS D 101−0.778 15.787 18.385 1.00 45.47 C ATOM 2289 NZ LYS D 101 0.071 15.69219.614 1.00 49.42 N ATOM 2290 C LYS D 101 −5.043 11.822 17.475 1.0032.87 C ATOM 2291 O LYS D 101 −5.813 11.880 18.448 1.00 32.25 O ATOM2292 N PHE D 102 −5.303 11.104 16.366 1.00 32.74 N ATOM 2293 CA PHE D102 −6.603 10.506 16.130 1.00 31.60 C ATOM 2294 CB PHE D 102 −7.27911.089 14.871 1.00 31.91 C ATOM 2295 CG PHE D 102 −7.714 12.529 15.0221.00 29.94 C ATOM 2296 CD1 PHE D 102 −9.004 12.848 15.414 1.00 29.78 CATOM 2297 CE1 PHE D 102 −9.402 14.211 15.537 1.00 24.97 C ATOM 2298 CZPHE D 102 −8.488 15.235 15.305 1.00 30.76 C ATOM 2299 CE2 PHE D 102−7.204 14.894 14.901 1.00 31.66 C ATOM 2300 CD2 PHE D 102 −6.840 13.56614.763 1.00 29.03 C ATOM 2301 C PHE D 102 −6.491 9.005 16.040 1.00 32.14C ATOM 2302 O PHE D 102 −7.504 8.304 16.084 1.00 32.25 O ATOM 2303 N GLYD 103 −5.275 8.480 15.911 1.00 31.31 N ATOM 2304 CA GLY D 103 −5.1747.038 15.785 1.00 31.79 C ATOM 2305 C GLY D 103 −5.567 6.419 14.444 1.0031.97 C ATOM 2306 O GLY D 103 −5.626 5.206 14.333 1.00 32.46 O ATOM 2307N GLU D 104 −5.772 7.254 13.424 1.00 31.27 N ATOM 2308 CA GLU D 104−6.165 6.798 12.103 1.00 32.35 C ATOM 2309 CB GLU D 104 −7.700 6.59712.055 1.00 31.98 C ATOM 2310 CG GLU D 104 −8.414 7.801 12.597 1.0037.23 C ATOM 2311 CD GLU D 104 −9.943 7.678 12.652 1.00 39.72 C ATOM2312 OE1 GLU D 104 −10.592 8.690 13.160 1.00 49.09 O ATOM 2313 OE2 GLU D104 −10.461 6.616 12.183 1.00 47.00 O ATOM 2314 C GLU D 104 −5.777 7.88711.094 1.00 28.30 C ATOM 2315 O GLU D 104 −5.610 9.058 11.457 1.00 27.32O ATOM 2316 N CYS D 105 −5.711 7.505 9.823 1.00 26.03 N ATOM 2317 CA CYSD 105 −5.317 8.438 8.770 1.00 24.64 C ATOM 2318 CB CYS D 105 −3.7948.380 8.639 1.00 24.89 C ATOM 2319 SG CYS D 105 −3.126 9.266 7.198 1.0024.05 S ATOM 2320 C CYS D 105 −5.989 7.928 7.501 1.00 25.33 C ATOM 2321O CYS D 105 −6.010 6.721 7.249 1.00 24.40 O ATOM 2322 N SER D 106 −6.6198.836 6.741 1.00 25.56 N ATOM 2323 CA SER D 106 −7.389 8.422 5.548 1.0026.47 C ATOM 2324 CB SER D 106 −8.516 9.453 5.249 1.00 26.24 C ATOM 2325OG SER D 106 −9.360 9.627 6.387 1.00 28.23 O ATOM 2326 C SER D 106−6.556 8.272 4.293 1.00 25.71 C ATOM 2327 O SER D 106 −7.097 7.880 3.2841.00 25.71 O ATOM 2328 N ASN D 107 −5.249 8.580 4.324 1.00 26.46 N ATOM2329 CA ASN D 107 −4.446 8.453 3.098 1.00 25.74 C ATOM 2330 CB ASN D 107−3.369 9.531 3.066 1.00 26.14 C ATOM 2331 CG ASN D 107 −2.628 9.6081.732 1.00 26.49 C ATOM 2332 OD1 ASN D 107 −2.882 8.825 0.829 1.00 26.10O ATOM 2333 ND2 ASN D 107 −1.747 10.610 1.599 1.00 25.07 N ATOM 2334 CASN D 107 −3.799 7.076 2.986 1.00 26.04 C ATOM 2335 O ASN D 107 −2.8296.795 3.679 1.00 24.98 O ATOM 2336 N LYS D 108 −4.287 6.235 2.078 1.0026.11 N ATOM 2337 CA LYS D 108 −3.702 4.897 1.874 1.00 27.13 C ATOM 2338CB LYS D 108 −4.374 4.196 0.702 1.00 27.98 C ATOM 2339 CG LYS D 108−5.821 3.823 0.946 1.00 28.66 C ATOM 2340 CD LYS D 108 −6.383 2.992−0.222 1.00 28.13 C ATOM 2341 CE LYS D 108 −7.909 3.041 −0.137 1.0029.83 C ATOM 2342 NZ LYS D 108 −8.548 2.711 −1.468 1.00 33.21 N ATOM2343 C LYS D 108 −2.236 5.019 1.559 1.00 28.60 C ATOM 2344 O LYS D 108−1.474 4.091 1.797 1.00 28.74 O ATOM 2345 N GLU D 109 −1.833 6.181 1.0401.00 28.07 N ATOM 2346 CA GLU D 109 −0.454 6.365 0.587 1.00 29.49 C ATOM2347 CB GLU D 109 −0.418 6.922 −0.872 1.00 29.49 C ATOM 2348 CG GLU D109 −0.531 5.937 −2.016 1.00 33.84 C ATOM 2349 CD GLU D 109 −1.877 5.272−2.118 1.00 38.05 C ATOM 2350 OE1 GLU D 109 −2.892 5.951 −2.409 1.0037.86 O ATOM 2351 OE2 GLU D 109 −1.903 4.025 −1.918 1.00 43.82 O ATOM2352 C GLU D 109 0.234 7.360 1.531 1.00 27.85 C ATOM 2353 O GLU D 1091.170 8.038 1.126 1.00 27.90 O ATOM 2354 N CYS D 110 −0.224 7.468 2.7941.00 27.24 N ATOM 2355 CA CYS D 110 0.349 8.464 3.668 1.00 26.45 C ATOM2356 CB CYS D 110 −0.217 8.424 5.110 1.00 26.19 C ATOM 2357 SG CYS D 1100.473 9.819 6.015 1.00 26.60 S ATOM 2358 C CYS D 110 1.861 8.236 3.7571.00 26.83 C ATOM 2359 O CYS D 110 2.306 7.136 4.093 1.00 27.21 O ATOM2360 N PRO D 111 2.644 9.264 3.464 1.00 28.24 N ATOM 2361 CA PRO D 1114.100 9.026 3.588 1.00 29.52 C ATOM 2362 CB PRO D 111 4.693 9.997 2.5711.00 29.24 C ATOM 2363 CG PRO D 111 3.697 11.231 2.593 1.00 29.52 C ATOM2364 CD PRO D 111 2.314 10.617 2.940 1.00 28.03 C ATOM 2365 C PRO D 1114.652 9.291 5.006 1.00 30.98 C ATOM 2366 O PRO D 111 5.844 9.085 5.2541.00 30.98 O ATOM 2367 N PHE D 112 3.804 9.736 5.928 1.00 30.89 N ATOM2368 CA PHE D 112 4.269 10.140 7.250 1.00 31.40 C ATOM 2369 CB PHE D 1123.488 11.400 7.720 1.00 30.20 C ATOM 2370 CG PHE D 112 3.666 12.5926.808 1.00 31.21 C ATOM 2371 CD1 PHE D 112 4.830 13.347 6.840 1.00 29.10C ATOM 2372 CE1 PHE D 112 4.997 14.422 5.991 1.00 29.55 C ATOM 2373 CZPHE D 112 3.956 14.776 5.080 1.00 30.53 C ATOM 2374 CE2 PHE D 112 2.78714.019 5.060 1.00 29.65 C ATOM 2375 CD2 PHE D 112 2.657 12.959 5.9021.00 29.41 C ATOM 2376 C PHE D 112 4.207 8.961 8.248 1.00 32.22 C ATOM2377 O PHE D 112 3.457 7.988 8.060 1.00 31.82 O ATOM 2378 N LEU D 1135.006 9.029 9.317 1.00 32.63 N ATOM 2379 CA LEU D 113 5.022 7.932 10.2981.00 33.39 C ATOM 2380 CB LEU D 113 6.094 8.155 11.371 1.00 33.96 C ATOM2381 CG LEU D 113 7.531 8.394 10.944 1.00 36.30 C ATOM 2382 CD1 LEU D113 8.354 8.768 12.166 1.00 38.73 C ATOM 2383 CD2 LEU D 113 8.092 7.13810.288 1.00 40.51 C ATOM 2384 C LEU D 113 3.682 7.730 11.012 1.00 33.17C ATOM 2385 O LEU D 113 3.125 8.664 11.575 1.00 32.95 O ATOM 2386 N HISD 114 3.226 6.489 11.016 1.00 33.23 N ATOM 2387 CA HIS D 114 2.100 6.06911.799 1.00 35.48 C ATOM 2388 CB HIS D 114 1.117 5.267 10.947 1.00 34.35C ATOM 2389 CG HIS D 114 0.415 6.058 9.871 1.00 30.91 C ATOM 2390 ND1HIS D 114 −0.475 5.460 9.007 1.00 30.62 N ATOM 2391 CE1 HIS D 114 −0.9616.359 8.166 1.00 29.38 C ATOM 2392 NE2 HIS D 114 −0.466 7.543 8.486 1.0021.78 N ATOM 2393 CD2 HIS D 114 0.420 7.374 9.546 1.00 25.39 C ATOM 2394C HIS D 114 2.577 5.228 13.001 1.00 37.49 C ATOM 2395 O HIS D 114 2.7694.011 12.893 1.00 38.30 O ATOM 2396 N ILE D 115 2.744 5.897 14.124 1.0040.28 N ATOM 2397 CA ILE D 115 3.278 5.292 15.358 1.00 44.28 C ATOM 2398CB ILE D 115 4.306 6.217 16.026 1.00 43.85 C ATOM 2399 CG1 ILE D 1155.492 6.454 15.092 1.00 43.41 C ATOM 2400 CD1 ILE D 115 6.188 7.70415.411 1.00 43.55 C ATOM 2401 CG2 ILE D 115 4.798 5.626 17.367 1.0045.91 C ATOM 2402 C ILE D 115 2.145 5.013 16.347 1.00 46.74 C ATOM 2403O ILE D 115 1.410 5.930 16.739 1.00 45.72 O ATOM 2404 N ASP D 116 2.0093.739 16.714 1.00 50.52 N ATOM 2405 CA ASP D 116 0.967 3.299 17.636 1.0054.53 C ATOM 2406 CB ASP D 116 0.748 1.815 17.497 1.00 54.79 C ATOM 2407CG ASP D 116 −0.004 1.487 16.252 1.00 57.65 C ATOM 2408 OD1 ASP D 116−0.920 2.284 15.908 1.00 58.31 O ATOM 2409 OD2 ASP D 116 0.332 0.45915.605 1.00 60.82 O ATOM 2410 C ASP D 116 1.257 3.653 19.082 1.00 57.26C ATOM 2411 O ASP D 116 2.430 3.687 19.507 1.00 57.07 O ATOM 2412 N PROD 117 0.187 3.944 19.844 1.00 59.98 N ATOM 2413 CA PRO D 117 0.354 4.42921.206 1.00 62.24 C ATOM 2414 CB PRO D 117 −1.063 4.434 21.747 1.0062.12 C ATOM 2415 CG PRO D 117 −1.913 4.600 20.533 1.00 61.61 C ATOM2416 CD PRO D 117 −1.233 3.827 19.468 1.00 60.37 C ATOM 2417 C PRO D 1171.253 3.461 21.965 1.00 64.67 C ATOM 2418 O PRO D 117 1.000 2.237 21.9931.00 64.83 O ATOM 2419 N GLU D 118 2.326 4.029 22.514 1.00 67.27 N ATOM2420 CA GLU D 118 3.477 3.280 23.006 1.00 69.59 C ATOM 2421 CB GLU D 1184.684 4.230 23.201 1.00 70.33 C ATOM 2422 CG GLU D 118 5.298 4.83621.899 1.00 73.39 C ATOM 2423 CD GLU D 118 4.568 6.103 21.334 1.00 76.34C ATOM 2424 OE1 GLU D 118 5.246 7.142 21.133 1.00 78.16 O ATOM 2425 OE2GLU D 118 3.342 6.068 21.065 1.00 76.31 O ATOM 2426 C GLU D 118 3.0912.594 24.317 1.00 70.03 C ATOM 2427 O GLU D 118 2.772 1.396 24.331 1.0070.42 O ATOM 2428 OXT GLU D 118 3.057 3.230 25.381 1.00 70.37 O ATOM2429 ZN ZN D 502 −0.941 9.474 7.886 1.00 26.96 ZN ATOM 2430 ZN ZN D 50112.470 23.684 4.582 1.00 38.67 ZN ATOM 2431 N HIS E 58 −45.599 5.932−6.806 1.00 42.25 N ATOM 2432 CA HIS E 58 −44.990 6.748 −5.741 1.0041.89 C ATOM 2433 CB HIS E 58 −43.463 6.785 −5.831 1.00 44.50 C ATOM2434 CG HIS E 58 −42.795 6.886 −4.479 1.00 50.77 C ATOM 2435 ND1 HIS E58 −43.456 7.346 −3.347 1.00 54.95 N ATOM 2436 CE1 HIS E 58 −42.6297.341 −2.319 1.00 56.42 C ATOM 2437 NE2 HIS E 58 −41.448 6.908 −2.7371.00 57.08 N ATOM 2438 CD2 HIS E 58 −41.527 6.607 −4.081 1.00 54.69 CATOM 2439 C HIS E 58 −45.544 8.155 −5.678 1.00 39.42 C ATOM 2440 O HIS E58 −46.314 8.545 −6.529 1.00 39.21 O ATOM 2441 N HIS E 59 −45.137 8.891−4.639 1.00 36.77 N ATOM 2442 CA HIS E 59 −45.638 10.226 −4.323 1.0034.79 C ATOM 2443 CB HIS E 59 −45.422 10.533 −2.828 1.00 34.59 C ATOM2444 CG HIS E 59 −46.395 9.818 −1.940 1.00 33.03 C ATOM 2445 ND1 HIS E59 −47.619 10.358 −1.596 1.00 32.36 N ATOM 2446 CE1 HIS E 59 −48.2849.494 −0.853 1.00 31.07 C ATOM 2447 NE2 HIS E 59 −47.546 8.412 −0.7121.00 33.32 N ATOM 2448 CD2 HIS E 59 −46.366 8.577 −1.404 1.00 33.19 CATOM 2449 C HIS E 59 −45.044 11.294 −5.192 1.00 33.88 C ATOM 2450 O HISE 59 −45.621 12.347 −5.359 1.00 34.21 O ATOM 2451 N MET E 60 −43.86811.030 −5.751 1.00 33.64 N ATOM 2452 CA MET E 60 −43.150 12.064 −6.4561.00 32.83 C ATOM 2453 CB MET E 60 −41.660 12.062 −6.014 1.00 33.04 CATOM 2454 CG MET E 60 −41.453 12.437 −4.513 1.00 31.91 C ATOM 2455 SDMET E 60 −41.776 14.194 −4.217 1.00 32.73 S ATOM 2456 CE MET E 60−40.473 15.014 −5.195 1.00 37.28 C ATOM 2457 C MET E 60 −43.287 11.794−7.946 1.00 32.82 C ATOM 2458 O MET E 60 −43.281 10.640 −8.378 1.0031.69 O ATOM 2459 N SER E 61 −43.409 12.856 −8.720 1.00 34.88 N ATOM2460 CA SER E 61 −43.525 12.717 −10.180 1.00 36.77 C ATOM 2461 CB SER E61 −43.851 14.048 −10.771 1.00 36.98 C ATOM 2462 OG SER E 61 −42.77714.923 −10.515 1.00 36.64 O ATOM 2463 C SER E 61 −42.240 12.186 −10.8261.00 38.65 C ATOM 2464 O SER E 61 −42.276 11.508 −11.861 1.00 38.84 OATOM 2465 N GLY E 62 −41.109 12.548 −10.238 1.00 38.90 N ATOM 2466 CAGLY E 62 −39.821 11.937 −10.565 1.00 42.02 C ATOM 2467 C GLY E 62−38.915 12.104 −9.370 1.00 42.64 C ATOM 2468 O GLY E 62 −39.227 12.872−8.468 1.00 42.24 O ATOM 2469 N GLU E 63 −37.796 11.393 −9.347 1.0045.02 N ATOM 2470 CA GLU E 63 −36.847 11.545 −8.225 1.00 47.21 C ATOM2471 CB GLU E 63 −36.811 10.301 −7.315 1.00 47.94 C ATOM 2472 CG GLU E63 −36.103 9.079 −7.946 1.00 50.89 C ATOM 2473 CD GLU E 63 −35.983 7.892−7.000 1.00 52.10 C ATOM 2474 OE1 GLU E 63 −36.013 8.100 −5.750 1.0059.78 O ATOM 2475 OE2 GLU E 63 −35.856 6.753 −7.508 1.00 58.02 O ATOM2476 C GLU E 63 −35.450 11.851 −8.749 1.00 46.14 C ATOM 2477 O GLU E 63−35.088 11.464 −9.878 1.00 46.17 O ATOM 2478 N LYS E 64 −34.683 12.571−7.939 1.00 44.27 N ATOM 2479 CA LYS E 64 −33.270 12.750 −8.212 1.0042.93 C ATOM 2480 CB LYS E 64 −32.739 13.869 −7.367 1.00 41.82 C ATOM2481 CG LYS E 64 −33.343 15.218 −7.693 1.00 41.03 C ATOM 2482 CD LYS E64 −33.057 16.133 −6.512 1.00 41.77 C ATOM 2483 CE LYS E 64 −33.36817.576 −6.788 1.00 41.00 C ATOM 2484 NZ LYS E 64 −32.771 18.415 −5.7021.00 40.32 N ATOM 2485 C LYS E 64 −32.560 11.436 −7.918 1.00 42.50 CATOM 2486 O LYS E 64 −33.026 10.610 −7.135 1.00 44.38 O ATOM 2487 N THRE 65 −31.441 11.193 −8.562 1.00 42.38 N ATOM 2488 CA THR E 65 −30.8319.888 −8.402 1.00 41.77 C ATOM 2489 CB THR E 65 −30.720 9.186 −9.7601.00 42.28 C ATOM 2490 OG1 THR E 65 −30.159 10.128 −10.693 1.00 41.94 OATOM 2491 CG2 THR E 65 −32.135 8.713 −10.241 1.00 45.27 C ATOM 2492 CTHR E 65 −29.423 9.995 −7.862 1.00 40.59 C ATOM 2493 O THR E 65 −28.8498.977 −7.475 1.00 40.78 O ATOM 2494 N VAL E 66 −28.842 11.193 −7.9051.00 38.83 N ATOM 2495 CA VAL E 66 −27.426 11.331 −7.492 1.00 37.55 CATOM 2496 CB VAL E 66 −26.459 11.437 −8.729 1.00 38.38 C ATOM 2497 CG1VAL E 66 −25.006 11.254 −8.300 1.00 37.81 C ATOM 2498 CG2 VAL E 66−26.794 10.360 −9.780 1.00 38.40 C ATOM 2499 C VAL E 66 −27.227 12.484−6.511 1.00 35.67 C ATOM 2500 O VAL E 66 −27.741 13.564 −6.731 1.0035.07 O ATOM 2501 N VAL E 67 −26.471 12.247 −5.427 1.00 35.49 N ATOM2502 CA VAL E 67 −26.180 13.321 −4.440 1.00 33.32 C ATOM 2503 CB VAL E67 −25.455 12.741 −3.186 1.00 34.57 C ATOM 2504 CG1 VAL E 67 −25.03813.845 −2.204 1.00 32.91 C ATOM 2505 CG2 VAL E 67 −26.283 11.653 −2.5071.00 34.32 C ATOM 2506 C VAL E 67 −25.326 14.407 −5.084 1.00 33.24 CATOM 2507 O VAL E 67 −24.399 14.102 −5.828 1.00 33.82 O ATOM 2508 N CYSE 68 −25.604 15.669 −4.811 1.00 31.69 N ATOM 2509 CA CYS E 68 −24.79916.744 −5.313 1.00 31.28 C ATOM 2510 CB CYS E 68 −25.538 18.035 −5.0751.00 29.96 C ATOM 2511 SG CYS E 68 −24.739 19.465 −5.730 1.00 33.39 SATOM 2512 C CYS E 68 −23.381 16.862 −4.647 1.00 31.68 C ATOM 2513 O CYSE 68 −23.271 17.214 −3.467 1.00 28.47 O ATOM 2514 N LYS E 69 −22.32516.598 −5.431 1.00 31.61 N ATOM 2515 CA LYS E 69 −20.908 16.763 −5.0171.00 32.83 C ATOM 2516 CB LYS E 69 −20.027 16.837 −6.279 1.00 33.94 CATOM 2517 CG LYS E 69 −19.380 15.596 −6.682 1.00 36.27 C ATOM 2518 CDLYS E 69 −18.340 15.955 −7.751 1.00 36.61 C ATOM 2519 CE LYS E 69−16.997 16.551 −7.151 1.00 35.02 C ATOM 2520 NZ LYS E 69 −16.668 17.768−7.999 1.00 34.32 N ATOM 2521 C LYS E 69 −20.618 18.068 −4.349 1.0032.43 C ATOM 2522 O LYS E 69 −19.978 18.119 −3.327 1.00 33.76 O ATOM2523 N HIS E 70 −20.993 19.132 −5.029 1.00 32.65 N ATOM 2524 CA HIS E 70−20.764 20.507 −4.616 1.00 34.13 C ATOM 2525 CB HIS E 70 −21.208 21.475−5.716 1.00 35.61 C ATOM 2526 CG HIS E 70 −20.401 21.362 −6.974 1.0041.83 C ATOM 2527 ND1 HIS E 70 −20.975 21.215 −8.219 1.00 44.87 N ATOM2528 CE1 HIS E 70 −20.021 21.107 −9.131 1.00 46.74 C ATOM 2529 NE2 HIS E70 −18.850 21.169 −8.521 1.00 46.66 N ATOM 2530 CD2 HIS E 70 −19.05721.348 −7.173 1.00 45.07 C ATOM 2531 C HIS E 70 −21.499 20.875 −3.3751.00 33.85 C ATOM 2532 O HIS E 70 −20.965 21.612 −2.540 1.00 32.81 OATOM 2533 N TRP E 71 −22.735 20.382 −3.234 1.00 32.72 N ATOM 2534 CA TRPE 71 −23.473 20.633 −1.999 1.00 31.55 C ATOM 2535 CB TRP E 71 −24.89820.093 −2.128 1.00 31.78 C ATOM 2536 CG TRP E 71 −25.618 20.081 −0.8631.00 30.88 C ATOM 2537 CD1 TRP E 71 −26.208 21.145 −0.255 1.00 32.24 CATOM 2538 NE1 TRP E 71 −26.752 20.766 0.939 1.00 30.42 N ATOM 2539 CE2TRP E 71 −26.545 19.423 1.119 1.00 31.60 C ATOM 2540 CD2 TRP E 71−25.810 18.959 0.001 1.00 31.97 C ATOM 2541 CE3 TRP E 71 −25.453 17.599−0.064 1.00 29.83 C ATOM 2542 CZ3 TRP E 71 −25.828 16.755 0.982 1.0031.73 C ATOM 2543 CH2 TRP E 71 −26.576 17.246 2.082 1.00 31.68 C ATOM2544 CZ2 TRP E 71 −26.932 18.579 2.164 1.00 33.50 C ATOM 2545 C TRP E 71−22.779 19.988 −0.793 1.00 31.55 C ATOM 2546 O TRP E 71 −22.696 20.5880.273 1.00 31.49 O ATOM 2547 N LEU E 72 −22.324 18.753 −0.940 1.00 31.49N ATOM 2548 CA LEU E 72 −21.521 18.104 0.095 1.00 33.29 C ATOM 2549 CBLEU E 72 −20.882 16.817 −0.408 1.00 32.05 C ATOM 2550 CG LEU E 72−21.709 15.628 −0.834 1.00 33.40 C ATOM 2551 CD1 LEU E 72 −20.740 14.576−1.311 1.00 33.05 C ATOM 2552 CD2 LEU E 72 −22.533 15.074 0.324 1.0034.38 C ATOM 2553 C LEU E 72 −20.421 18.995 0.666 1.00 35.07 C ATOM 2554O LEU E 72 −20.179 18.977 1.889 1.00 34.12 O ATOM 2555 N ARG E 73−19.811 19.800 −0.211 1.00 36.81 N ATOM 2556 CA ARG E 73 −18.657 20.6170.109 1.00 40.54 C ATOM 2557 CB ARG E 73 −17.582 20.487 −0.995 1.0040.08 C ATOM 2558 CG ARG E 73 −17.188 19.023 −1.253 1.00 38.53 C ATOM2559 CD ARG E 73 −15.766 18.806 −1.829 1.00 42.91 C ATOM 2560 NE ARG E73 −14.721 19.373 −0.957 1.00 44.71 N ATOM 2561 CZ ARG E 73 −13.98820.441 −1.248 1.00 41.53 C ATOM 2562 NH1 ARG E 73 −14.110 21.056 −2.4181.00 38.99 N ATOM 2563 NH2 ARG E 73 −13.095 20.874 −0.366 1.00 39.88 NATOM 2564 C ARG E 73 −19.038 22.074 0.384 1.00 42.77 C ATOM 2565 O ARG E73 −18.175 22.881 0.710 1.00 44.16 O ATOM 2566 N GLY E 74 −20.336 22.3860.298 1.00 44.23 N ATOM 2567 CA GLY E 74 −20.858 23.741 0.583 1.00 46.05C ATOM 2568 C GLY E 74 −20.728 24.678 −0.610 1.00 46.86 C ATOM 2569 OGLY E 74 −20.793 25.910 −0.460 1.00 48.02 O ATOM 2570 N LEU E 75 −20.53224.104 −1.791 1.00 47.48 N ATOM 2571 CA LEU E 75 −20.302 24.871 −3.0201.00 48.84 C ATOM 2572 CB LEU E 75 −19.129 24.266 −3.816 1.00 49.51 CATOM 2573 CG LEU E 75 −17.738 24.086 −3.189 1.00 50.58 C ATOM 2574 CD1LEU E 75 −16.902 23.169 −4.073 1.00 50.57 C ATOM 2575 CD2 LEU E 75−17.066 25.434 −2.994 1.00 50.81 C ATOM 2576 C LEU E 75 −21.498 24.943−3.983 1.00 49.52 C ATOM 2577 O LEU E 75 −21.321 25.345 −5.153 1.0050.54 O ATOM 2578 N CYS E 76 −22.682 24.497 −3.561 1.00 48.50 N ATOM2579 CA CYS E 76 −23.841 24.558 −4.460 1.00 49.32 C ATOM 2580 CB CYS E76 −24.746 23.332 −4.338 1.00 49.22 C ATOM 2581 SG CYS E 76 −25.96623.095 −5.719 1.00 45.68 S ATOM 2582 C CYS E 76 −24.616 25.803 −4.1231.00 50.25 C ATOM 2583 O CYS E 76 −24.951 26.040 −2.956 1.00 50.15 OATOM 2584 N LYS E 77 −24.885 26.608 −5.145 1.00 51.41 N ATOM 2585 CA LYSE 77 −25.629 27.849 −4.945 1.00 52.98 C ATOM 2586 CB LYS E 77 −24.86829.022 −5.590 1.00 54.17 C ATOM 2587 CG LYS E 77 −23.520 29.356 −4.9101.00 55.63 C ATOM 2588 CD LYS E 77 −23.643 29.529 −3.369 1.00 59.35 CATOM 2589 CE LYS E 77 −22.265 29.528 −2.689 1.00 60.06 C ATOM 2590 NZLYS E 77 −22.296 28.836 −1.352 1.00 63.41 N ATOM 2591 C LYS E 77 −27.09227.775 −5.458 1.00 52.74 C ATOM 2592 O LYS E 77 −27.834 28.756 −5.3731.00 53.10 O ATOM 2593 N LYS E 78 −27.478 26.606 −5.971 1.00 52.29 NATOM 2594 CA LYS E 78 −28.781 26.376 −6.618 1.00 51.59 C ATOM 2595 CBLYS E 78 −28.629 25.314 −7.701 1.00 51.61 C ATOM 2596 CG LYS E 78−27.597 25.644 −8.736 1.00 55.37 C ATOM 2597 CD LYS E 78 −27.595 24.600−9.828 1.00 60.45 C ATOM 2598 CE LYS E 78 −26.265 24.629 −10.576 1.0064.73 C ATOM 2599 NZ LYS E 78 −26.241 23.689 −11.766 1.00 67.80 N ATOM2600 C LYS E 78 −29.925 25.946 −5.695 1.00 50.45 C ATOM 2601 O LYS E 78−31.070 25.859 −6.152 1.00 50.69 O ATOM 2602 N GLY E 79 −29.622 25.633−4.431 1.00 48.61 N ATOM 2603 CA GLY E 79 −30.626 25.169 −3.467 1.0046.20 C ATOM 2604 C GLY E 79 −31.582 24.117 −4.026 1.00 45.27 C ATOM2605 O GLY E 79 −31.149 23.109 −4.600 1.00 42.86 O ATOM 2606 N ASP E 80−32.889 24.387 −3.878 1.00 45.12 N ATOM 2607 CA ASP E 80 −33.971 23.474−4.336 1.00 44.97 C ATOM 2608 CB ASP E 80 −35.331 23.877 −3.733 1.0045.06 C ATOM 2609 CG ASP E 80 −35.385 23.621 −2.241 1.00 45.92 C ATOM2610 OD1 ASP E 80 −34.552 22.805 −1.797 1.00 50.22 O ATOM 2611 OD2 ASP E80 −36.209 24.215 −1.505 1.00 43.28 O ATOM 2612 C ASP E 80 −34.05523.260 −5.850 1.00 45.13 C ATOM 2613 O ASP E 80 −34.584 22.247 −6.2981.00 44.46 O ATOM 2614 N GLN E 81 −33.486 24.186 −6.620 1.00 45.80 NATOM 2615 CA GLN E 81 −33.488 24.107 −8.089 1.00 46.94 C ATOM 2616 CBGLN E 81 −33.388 25.513 −8.722 1.00 47.91 C ATOM 2617 CG GLN E 81−34.653 26.382 −8.648 1.00 49.80 C ATOM 2618 CD GLN E 81 −35.031 26.756−7.225 1.00 52.50 C ATOM 2619 OE1 GLN E 81 −34.201 27.259 −6.450 1.0056.42 O ATOM 2620 NE2 GLN E 81 −36.271 26.508 −6.866 1.00 53.27 N ATOM2621 C GLN E 81 −32.354 23.226 −8.628 1.00 46.85 C ATOM 2622 O GLN E 81−32.232 23.038 −9.840 1.00 47.31 O ATOM 2623 N CYS E 82 −31.532 22.660−7.741 1.00 46.00 N ATOM 2624 CA CYS E 82 −30.473 21.759 −8.197 1.0044.71 C ATOM 2625 CB CYS E 82 −29.479 21.471 −7.058 1.00 44.58 C ATOM2626 SG CYS E 82 −28.029 20.574 −7.678 1.00 44.34 S ATOM 2627 C CYS E 82−31.048 20.446 −8.726 1.00 44.24 C ATOM 2628 O CYS E 82 −32.071 19.975−8.225 1.00 44.60 O ATOM 2629 N GLU E 83 −30.404 19.860 −9.739 1.0043.02 N ATOM 2630 CA GLU E 83 −30.808 18.571 −10.321 1.00 42.89 C ATOM2631 CB GLU E 83 −30.223 18.471 −11.729 1.00 43.36 C ATOM 2632 CG GLU E83 −29.088 19.514 −11.963 1.00 47.27 C ATOM 2633 CD GLU E 83 −28.17619.165 −13.153 1.00 48.75 C ATOM 2634 OE1 GLU E 83 −27.193 19.932−13.395 1.00 55.39 O ATOM 2635 OE2 GLU E 83 −28.415 18.114 −13.830 1.0055.23 O ATOM 2636 C GLU E 83 −30.335 17.384 −9.494 1.00 39.93 C ATOM2637 O GLU E 83 −30.741 16.215 −9.687 1.00 39.21 O ATOM 2638 N PHE E 84−29.430 17.670 −8.570 1.00 37.89 N ATOM 2639 CA PHE E 84 −28.891 16.613−7.756 1.00 35.71 C ATOM 2640 CB PHE E 84 −27.343 16.609 −7.806 1.0035.62 C ATOM 2641 CG PHE E 84 −26.766 16.461 −9.205 1.00 36.55 C ATOM2642 CD1 PHE E 84 −26.238 17.561 −9.868 1.00 35.78 C ATOM 2643 CE1 PHE E84 −25.683 17.440 −11.182 1.00 38.26 C ATOM 2644 CZ PHE E 84 −25.64916.207 −11.803 1.00 38.82 C ATOM 2645 CE2 PHE E 84 −26.161 15.078−11.147 1.00 42.35 C ATOM 2646 CD2 PHE E 84 −26.716 15.210 −9.829 1.0039.76 C ATOM 2647 C PHE E 84 −29.455 16.778 −6.320 1.00 34.41 C ATOM2648 O PHE E 84 −29.864 17.860 −5.913 1.00 33.89 O ATOM 2649 N LEU E 85−29.455 15.676 −5.603 1.00 33.01 N ATOM 2650 CA LEU E 85 −29.962 15.539−4.242 1.00 34.42 C ATOM 2651 CB LEU E 85 −29.888 14.039 −3.909 1.0034.42 C ATOM 2652 CG LEU E 85 −30.854 12.999 −3.361 1.00 38.28 C ATOM2653 CD1 LEU E 85 −32.315 13.248 −3.771 1.00 39.00 C ATOM 2654 CD2 LEU E85 −30.402 11.593 −3.836 1.00 34.69 C ATOM 2655 C LEU E 85 −29.12216.367 −3.237 1.00 34.30 C ATOM 2656 O LEU E 85 −27.880 16.259 −3.1981.00 33.65 O ATOM 2657 N HIS E 86 −29.786 17.193 −2.434 1.00 33.63 NATOM 2658 CA HIS E 86 −29.142 17.847 −1.317 1.00 33.34 C ATOM 2659 CBHIS E 86 −29.541 19.304 −1.260 1.00 32.70 C ATOM 2660 CG HIS E 86−28.884 20.172 −2.295 1.00 31.14 C ATOM 2661 ND1 HIS E 86 −28.827 21.541−2.162 1.00 30.21 N ATOM 2662 CE1 HIS E 86 −28.204 22.066 −3.195 1.0031.04 C ATOM 2663 NE2 HIS E 86 −27.817 21.077 −3.983 1.00 27.66 N ATOM2664 CD2 HIS E 86 −28.236 19.883 −3.447 1.00 28.50 C ATOM 2665 C HIS E86 −29.508 17.096 −0.031 1.00 34.46 C ATOM 2666 O HIS E 86 −30.22717.602 0.834 1.00 34.31 O ATOM 2667 N GLU E 87 −29.018 15.860 0.059 1.0035.41 N ATOM 2668 CA GLU E 87 −29.192 15.005 1.212 1.00 37.64 C ATOM2669 CB GLU E 87 −30.511 14.229 1.121 1.00 37.29 C ATOM 2670 CG GLU E 87−30.694 13.235 2.264 1.00 38.59 C ATOM 2671 CD GLU E 87 −31.891 12.2802.135 1.00 38.23 C ATOM 2672 OE1 GLU E 87 −32.573 12.259 1.077 1.0035.85 O ATOM 2673 OE2 GLU E 87 −32.117 11.536 3.137 1.00 41.22 O ATOM2674 C GLU E 87 −28.040 13.999 1.175 1.00 39.03 C ATOM 2675 O GLU E 87−27.698 13.479 0.100 1.00 38.12 O ATOM 2676 N TYR E 88 −27.453 13.6832.329 1.00 40.99 N ATOM 2677 CA TYR E 88 −26.438 12.647 2.306 1.00 43.56C ATOM 2678 CB TYR E 88 −25.405 12.692 3.460 1.00 44.72 C ATOM 2679 CGTYR E 88 −24.238 11.718 3.169 1.00 47.61 C ATOM 2680 CD1 TYR E 88−23.255 12.023 2.216 1.00 49.16 C ATOM 2681 CE1 TYR E 88 −22.220 11.1101.913 1.00 48.23 C ATOM 2682 CZ TYR E 88 −22.190 9.907 2.524 1.00 44.96C ATOM 2683 OH TYR E 88 −21.205 9.042 2.249 1.00 49.62 O ATOM 2684 CE2TYR E 88 −23.132 9.561 3.470 1.00 49.06 C ATOM 2685 CD2 TYR E 88 −24.16110.464 3.790 1.00 48.49 C ATOM 2686 C TYR E 88 −27.123 11.341 2.243 1.0044.32 C ATOM 2687 O TYR E 88 −27.732 10.920 3.203 1.00 45.92 O ATOM 2688N ASP E 89 −27.039 10.698 1.093 1.00 45.86 N ATOM 2689 CA ASP E 89−27.430 9.313 0.980 1.00 47.31 C ATOM 2690 CB ASP E 89 −28.644 9.1710.048 1.00 46.75 C ATOM 2691 CG ASP E 89 −29.146 7.733 −0.071 1.00 47.59C ATOM 2692 OD1 ASP E 89 −28.410 6.765 0.237 1.00 46.06 O ATOM 2693 OD2ASP E 89 −30.306 7.566 −0.503 1.00 50.29 O ATOM 2694 C ASP E 89 −26.2218.580 0.428 1.00 48.29 C ATOM 2695 O ASP E 89 −25.901 8.717 −0.747 1.0047.55 O ATOM 2696 N MET E 90 −25.566 7.805 1.295 1.00 50.53 N ATOM 2697CA MET E 90 −24.346 7.060 0.956 1.00 53.26 C ATOM 2698 CB MET E 90−23.756 6.309 2.188 1.00 53.27 C ATOM 2699 CG MET E 90 −24.552 5.0532.647 1.00 56.70 C ATOM 2700 SD MET E 90 −24.136 4.344 4.281 1.00 58.92S ATOM 2701 CE MET E 90 −22.763 3.255 3.864 1.00 60.49 C ATOM 2702 C METE 90 −24.551 6.100 −0.214 1.00 52.16 C ATOM 2703 O MET E 90 −23.5815.736 −0.879 1.00 52.83 O ATOM 2704 N THR E 91 −25.810 5.715 −0.474 1.0051.03 N ATOM 2705 CA THR E 91 −26.135 4.762 −1.551 1.00 49.35 C ATOM2706 CB THR E 91 −27.402 3.887 −1.243 1.00 49.74 C ATOM 2707 OG1 THR E91 −28.539 4.732 −1.018 1.00 49.46 O ATOM 2708 CG2 THR E 91 −27.1723.001 −0.031 1.00 50.99 C ATOM 2709 C THR E 91 −26.377 5.443 −2.873 1.0047.57 C ATOM 2710 O THR E 91 −26.556 4.765 −3.900 1.00 47.97 O ATOM 2711N LYS E 92 −26.410 6.773 −2.870 1.00 44.84 N ATOM 2712 CA LYS E 92−26.694 7.493 −4.110 1.00 42.64 C ATOM 2713 CB LYS E 92 −28.060 8.202−4.052 1.00 42.47 C ATOM 2714 CG LYS E 92 −29.239 7.224 −4.140 1.0043.53 C ATOM 2715 CD LYS E 92 −30.550 7.958 −4.021 1.00 46.74 C ATOM2716 CE LYS E 92 −31.751 7.118 −4.485 1.00 49.77 C ATOM 2717 NZ LYS E 92−32.896 8.037 −4.867 1.00 50.02 N ATOM 2718 C LYS E 92 −25.573 8.457−4.501 1.00 40.10 C ATOM 2719 O LYS E 92 −25.796 9.458 −5.136 1.00 38.93O ATOM 2720 N MET E 93 −24.349 8.133 −4.122 1.00 39.27 N ATOM 2721 CAMET E 93 −23.235 9.034 −4.437 1.00 36.91 C ATOM 2722 CB MET E 93 −22.1198.773 −3.412 1.00 37.41 C ATOM 2723 CG MET E 93 −22.479 9.291 −1.9641.00 31.53 C ATOM 2724 SD MET E 93 −22.304 11.036 −1.841 1.00 28.70 SATOM 2725 CE MET E 93 −20.484 11.169 −1.694 1.00 34.53 C ATOM 2726 C METE 93 −22.765 8.825 −5.899 1.00 37.37 C ATOM 2727 O MET E 93 −22.9187.710 −6.447 1.00 36.91 O ATOM 2728 N PRO E 94 −22.165 9.857 −6.536 1.0036.94 N ATOM 2729 CA PRO E 94 −21.564 9.531 −7.838 1.00 37.19 C ATOM2730 CB PRO E 94 −21.254 10.895 −8.461 1.00 36.24 C ATOM 2731 CG PRO E94 −20.950 11.736 −7.389 1.00 38.23 C ATOM 2732 CD PRO E 94 −21.98811.296 −6.224 1.00 39.37 C ATOM 2733 C PRO E 94 −20.320 8.631 −7.8111.00 36.57 C ATOM 2734 O PRO E 94 −19.810 8.256 −6.737 1.00 35.69 O ATOM2735 N GLU E 95 −19.914 8.226 −9.014 1.00 35.80 N ATOM 2736 CA GLU E 95−18.753 7.391 −9.223 1.00 35.27 C ATOM 2737 CB GLU E 95 −18.713 6.907−10.675 1.00 35.38 C ATOM 2738 CG GLU E 95 −17.861 5.669 −10.825 1.0038.08 C ATOM 2739 CD GLU E 95 −17.766 5.134 −12.274 1.00 40.77 C ATOM2740 OE1 GLU E 95 −18.593 5.507 −13.149 1.00 46.42 O ATOM 2741 OE2 GLU E95 −16.839 4.316 −12.507 1.00 46.20 O ATOM 2742 C GLU E 95 −17.498 8.196−8.913 1.00 31.36 C ATOM 2743 O GLU E 95 −17.424 9.384 −9.207 1.00 31.21O ATOM 2744 N CYS E 96 −16.527 7.556 −8.294 1.00 29.43 N ATOM 2745 CACYS E 96 −15.284 8.265 −7.889 1.00 28.13 C ATOM 2746 CB CYS E 96 −14.5087.365 −6.971 1.00 27.21 C ATOM 2747 SG CYS E 96 −12.849 7.953 −6.5491.00 27.50 S ATOM 2748 C CYS E 96 −14.508 8.471 −9.175 1.00 27.70 C ATOM2749 O CYS E 96 −14.232 7.501 −9.836 1.00 27.84 O ATOM 2750 N TYR E 97−14.181 9.703 −9.531 1.00 26.25 N ATOM 2751 CA TYR E 97 −13.414 9.932−10.745 1.00 27.57 C ATOM 2752 CB TYR E 97 −13.183 11.447 −10.963 1.0027.83 C ATOM 2753 CG TYR E 97 −12.434 11.765 −12.280 1.00 27.33 C ATOM2754 CD1 TYR E 97 −13.144 11.989 −13.471 1.00 27.83 C ATOM 2755 CE1 TYRE 97 −12.478 12.267 −14.677 1.00 27.62 C ATOM 2756 CZ TYR E 97 −11.08212.321 −14.685 1.00 28.27 C ATOM 2757 OH TYR E 97 −10.432 12.605 −15.8801.00 25.71 O ATOM 2758 CE2 TYR E 97 −10.354 12.103 −13.511 1.00 24.85 CATOM 2759 CD2 TYR E 97 −11.038 11.817 −12.316 1.00 26.24 C ATOM 2760 CTYR E 97 −12.073 9.203 −10.758 1.00 28.02 C ATOM 2761 O TYR E 97 −11.6598.599 −11.805 1.00 27.69 O ATOM 2762 N PHE E 98 −11.400 9.205 −9.5931.00 28.03 N ATOM 2763 CA PHE E 98 −10.056 8.574 −9.539 1.00 28.74 CATOM 2764 CB PHE E 98 −9.209 9.067 −8.348 1.00 27.42 C ATOM 2765 CG PHEE 98 −8.924 10.529 −8.429 1.00 27.64 C ATOM 2766 CD1 PHE E 98 −7.87711.006 −9.197 1.00 23.70 C ATOM 2767 CE1 PHE E 98 −7.658 12.398 −9.3171.00 26.52 C ATOM 2768 CZ PHE E 98 −8.497 13.304 −8.674 1.00 28.09 CATOM 2769 CE2 PHE E 98 −9.562 12.831 −7.920 1.00 28.78 C ATOM 2770 CD2PHE E 98 −9.789 11.454 −7.817 1.00 28.89 C ATOM 2771 C PHE E 98 −10.1237.079 −9.657 1.00 29.39 C ATOM 2772 O PHE E 98 −9.326 6.464 −10.377 1.0029.21 O ATOM 2773 N TYR E 99 −11.082 6.463 −8.980 1.00 30.20 N ATOM 2774CA TYR E 99 −11.204 5.035 −9.147 1.00 31.46 C ATOM 2775 CB TYR E 99−12.314 4.476 −8.289 1.00 32.90 C ATOM 2776 CG TYR E 99 −12.154 3.001−8.112 1.00 35.08 C ATOM 2777 CD1 TYR E 99 −11.241 2.484 −7.198 1.0034.37 C ATOM 2778 CE1 TYR E 99 −11.089 1.106 −7.057 1.00 36.08 C ATOM2779 CZ TYR E 99 −11.825 0.251 −7.867 1.00 36.77 C ATOM 2780 OH TYR E 99−11.700 −1.119 −7.754 1.00 39.62 O ATOM 2781 CE2 TYR E 99 −12.712 0.738−8.781 1.00 38.21 C ATOM 2782 CD2 TYR E 99 −12.871 2.107 −8.916 1.0036.36 C ATOM 2783 C TYR E 99 −11.462 4.646 −10.616 1.00 32.82 C ATOM2784 O TYR E 99 −10.908 3.659 −11.120 1.00 32.79 O ATOM 2785 N SER E 100−12.332 5.389 −11.280 1.00 33.86 N ATOM 2786 CA SER E 100 −12.687 5.068−12.670 1.00 35.38 C ATOM 2787 CB SER E 100 −13.824 5.936 −13.129 1.0035.98 C ATOM 2788 OG SER E 100 −14.948 5.495 −12.418 1.00 42.18 O ATOM2789 C SER E 100 −11.552 5.261 −13.634 1.00 34.57 C ATOM 2790 O SER E100 −11.311 4.382 −14.485 1.00 35.38 O ATOM 2791 N LYS E 101 −10.8986.419 −13.544 1.00 33.48 N ATOM 2792 CA LYS E 101 −9.846 6.763 −14.4751.00 33.32 C ATOM 2793 CB LYS E 101 −9.693 8.273 −14.596 1.00 32.76 CATOM 2794 CG LYS E 101 −10.919 8.921 −15.140 1.00 35.61 C ATOM 2795 CDLYS E 101 −11.059 8.628 −16.629 1.00 39.82 C ATOM 2796 CE LYS E 101−12.355 9.151 −17.199 1.00 42.68 C ATOM 2797 NZ LYS E 101 −12.484 8.574−18.576 1.00 42.39 N ATOM 2798 C LYS E 101 −8.497 6.108 −14.191 1.0033.88 C ATOM 2799 O LYS E 101 −7.759 5.832 −15.139 1.00 33.90 O ATOM2800 N PHE E 102 −8.181 5.861 −12.912 1.00 32.56 N ATOM 2801 CA PHE E102 −6.835 5.447 −12.503 1.00 31.86 C ATOM 2802 CB PHE E 102 −6.2096.431 −11.495 1.00 31.71 C ATOM 2803 CG PHE E 102 −5.911 7.752 −12.0701.00 29.81 C ATOM 2804 CD1 PHE E 102 −4.669 8.009 −12.648 1.00 30.67 CATOM 2805 CE1 PHE E 102 −4.383 9.228 −13.206 1.00 31.08 C ATOM 2806 CZPHE E 102 −5.313 10.210 −13.239 1.00 29.85 C ATOM 2807 CE2 PHE E 102−6.592 9.960 −12.677 1.00 32.46 C ATOM 2808 CD2 PHE E 102 −6.855 8.741−12.088 1.00 30.80 C ATOM 2809 C PHE E 102 −6.867 4.069 −11.922 1.0032.42 C ATOM 2810 O PHE E 102 −5.820 3.478 −11.671 1.00 33.02 O ATOM2811 N GLY E 103 −8.068 3.525 −11.746 1.00 31.07 N ATOM 2812 CA GLY E103 −8.200 2.204 −11.153 1.00 31.68 C ATOM 2813 C GLY E 103 −7.805 2.110−9.684 1.00 31.41 C ATOM 2814 O GLY E 103 −7.611 1.003 −9.152 1.00 31.06O ATOM 2815 N GLU E 104 −7.663 3.257 −9.019 1.00 29.83 N ATOM 2816 CAGLU E 104 −7.265 3.253 −7.620 1.00 30.89 C ATOM 2817 CB GLU E 104 −5.7323.019 −7.469 1.00 29.78 C ATOM 2818 CG GLU E 104 −4.916 4.241 −7.7801.00 33.61 C ATOM 2819 CD GLU E 104 −3.398 4.038 −7.615 1.00 36.14 CATOM 2820 OE1 GLU E 104 −2.709 3.917 −8.663 1.00 46.90 O ATOM 2821 OE2GLU E 104 −2.887 3.988 −6.469 1.00 39.91 O ATOM 2822 C GLU E 104 −7.6904.595 −7.001 1.00 29.61 C ATOM 2823 O GLU E 104 −7.924 5.573 −7.706 1.0028.68 O ATOM 2824 N CYS E 105 −7.825 4.607 −5.671 1.00 29.11 N ATOM 2825CA CYS E 105 −8.246 5.809 −4.944 1.00 28.00 C ATOM 2826 CB CYS E 105−9.773 5.777 −4.754 1.00 28.22 C ATOM 2827 SG CYS E 105 −10.400 7.210−3.819 1.00 26.77 S ATOM 2828 C CYS E 105 −7.535 5.815 −3.584 1.00 27.95C ATOM 2829 O CYS E 105 −7.514 4.801 −2.897 1.00 25.98 O ATOM 2830 N SERE 106 −6.951 6.947 −3.213 1.00 27.07 N ATOM 2831 CA SER E 106 −6.1057.032 −1.999 1.00 27.68 C ATOM 2832 CB SER E 106 −5.147 8.214 −2.1061.00 28.93 C ATOM 2833 OG SER E 106 −4.158 8.061 −3.082 1.00 32.26 OATOM 2834 C SER E 106 −6.926 7.262 −0.708 1.00 27.48 C ATOM 2835 O SER E106 −6.392 7.202 0.389 1.00 25.89 O ATOM 2836 N ASN E 107 −8.224 7.543−0.847 1.00 27.00 N ATOM 2837 CA ASN E 107 −9.022 7.880 0.340 1.00 27.38C ATOM 2838 CB ASN E 107 −10.085 8.933 −0.017 1.00 25.51 C ATOM 2839 CGASN E 107 −10.890 9.409 1.197 1.00 27.22 C ATOM 2840 OD1 ASN E 107−10.602 9.029 2.353 1.00 25.23 O ATOM 2841 ND2 ASN E 107 −11.888 10.2530.951 1.00 23.13 N ATOM 2842 C ASN E 107 −9.615 6.620 0.922 1.00 26.72 CATOM 2843 O ASN E 107 −10.527 6.051 0.323 1.00 27.32 O ATOM 2844 N LYS E108 −9.112 6.171 2.083 1.00 27.29 N ATOM 2845 CA LYS E 108 −9.675 4.9672.740 1.00 28.64 C ATOM 2846 CB LYS E 108 −9.005 4.634 4.084 1.00 29.14C ATOM 2847 CG LYS E 108 −7.538 4.411 4.047 1.00 32.85 C ATOM 2848 CDLYS E 108 −7.002 4.055 5.424 1.00 35.90 C ATOM 2849 CE LYS E 108 −5.5124.069 5.365 1.00 36.28 C ATOM 2850 NZ LYS E 108 −4.896 4.177 6.709 1.0038.68 N ATOM 2851 C LYS E 108 −11.169 5.115 3.022 1.00 28.54 C ATOM 2852O LYS E 108 −11.874 4.132 3.143 1.00 28.63 O ATOM 2853 N GLU E 109−11.635 6.345 3.166 1.00 28.33 N ATOM 2854 CA GLU E 109 −13.047 6.5753.462 1.00 29.24 C ATOM 2855 CB GLU E 109 −13.216 7.516 4.691 1.00 30.12C ATOM 2856 CG GLU E 109 −12.867 6.879 6.081 1.00 35.42 C ATOM 2857 CDGLU E 109 −11.375 6.836 6.374 1.00 39.45 C ATOM 2858 OE1 GLU E 109−10.711 7.883 6.247 1.00 43.20 O ATOM 2859 OE2 GLU E 109 −10.867 5.7566.753 1.00 42.90 O ATOM 2860 C GLU E 109 −13.729 7.224 2.273 1.00 26.67C ATOM 2861 O GLU E 109 −14.689 7.956 2.466 1.00 27.77 O ATOM 2862 N CYSE 110 −13.258 6.987 1.039 1.00 25.08 N ATOM 2863 CA CYS E 110 −13.9327.567 −0.125 1.00 22.73 C ATOM 2864 CB CYS E 110 −13.376 7.014 −1.4731.00 22.38 C ATOM 2865 SG CYS E 110 −14.027 7.983 −2.730 1.00 25.05 SATOM 2866 C CYS E 110 −15.435 7.227 −0.065 1.00 23.60 C ATOM 2867 O CYSE 110 −15.792 6.066 0.033 1.00 22.90 O ATOM 2868 N PRO E 111 −16.3028.231 −0.103 1.00 25.41 N ATOM 2869 CA PRO E 111 −17.756 7.947 −0.1731.00 26.31 C ATOM 2870 CB PRO E 111 −18.338 9.189 0.451 1.00 25.57 CATOM 2871 CG PRO E 111 −17.444 10.247 −0.107 1.00 26.34 C ATOM 2872 CDPRO E 111 −16.056 9.690 −0.017 1.00 24.13 C ATOM 2873 C PRO E 111−18.303 7.806 −1.607 1.00 28.09 C ATOM 2874 O PRO E 111 −19.532 7.606−1.781 1.00 29.35 O ATOM 2875 N PHE E 112 −17.433 7.912 −2.620 1.0027.81 N ATOM 2876 CA PHE E 112 −17.882 7.841 −4.035 1.00 28.90 C ATOM2877 CB PHE E 112 −17.134 8.827 −4.915 1.00 27.89 C ATOM 2878 CG PHE E112 −17.352 10.241 −4.519 1.00 29.43 C ATOM 2879 CD1 PHE E 112 −18.53410.897 −4.864 1.00 29.20 C ATOM 2880 CE1 PHE E 112 −18.766 12.200 −4.4651.00 31.44 C ATOM 2881 CZ PHE E 112 −17.793 12.893 −3.678 1.00 33.51 CATOM 2882 CE2 PHE E 112 −16.595 12.222 −3.336 1.00 36.00 C ATOM 2883 CD2PHE E 112 −16.403 10.905 −3.756 1.00 32.00 C ATOM 2884 C PHE E 112−17.782 6.434 −4.538 1.00 30.08 C ATOM 2885 O PHE E 112 −17.062 5.634−3.968 1.00 29.81 O ATOM 2886 N LEU E 113 −18.581 6.077 −5.546 1.0032.91 N ATOM 2887 CA LEU E 113 −18.669 4.649 −5.892 1.00 35.90 C ATOM2888 CB LEU E 113 −19.833 4.379 −6.828 1.00 37.47 C ATOM 2889 CG LEU E113 −21.292 4.429 −6.377 1.00 41.02 C ATOM 2890 CD1 LEU E 113 −21.8763.209 −7.053 1.00 44.71 C ATOM 2891 CD2 LEU E 113 −21.536 4.386 −4.8401.00 43.90 C ATOM 2892 C LEU E 113 −17.391 4.132 −6.538 1.00 36.02 CATOM 2893 O LEU E 113 −16.829 4.764 −7.434 1.00 36.35 O ATOM 2894 N HISE 114 −16.931 2.977 −6.089 1.00 36.99 N ATOM 2895 CA HIS E 114 −15.7502.409 −6.678 1.00 37.82 C ATOM 2896 CB HIS E 114 −14.693 2.014 −5.6141.00 36.44 C ATOM 2897 CG HIS E 114 −13.917 3.183 −5.031 1.00 30.06 CATOM 2898 ND1 HIS E 114 −12.967 3.009 −4.046 1.00 27.67 N ATOM 2899 CE1HIS E 114 −12.448 4.177 −3.706 1.00 29.37 C ATOM 2900 NE2 HIS E 114−12.992 5.119 −4.459 1.00 21.70 N ATOM 2901 CD2 HIS E 114 −13.942 4.521−5.284 1.00 28.54 C ATOM 2902 C HIS E 114 −16.206 1.255 −7.575 1.0041.48 C ATOM 2903 O HIS E 114 −16.540 0.141 −7.109 1.00 41.75 O ATOM2904 N ILE E 115 −16.225 1.542 −8.874 1.00 45.09 N ATOM 2905 CA ILE E115 −16.770 0.592 −9.829 1.00 48.98 C ATOM 2906 CB ILE E 115 −17.8791.233 −10.682 1.00 48.73 C ATOM 2907 CG1 ILE E 115 −19.018 1.650 −9.7691.00 49.30 C ATOM 2908 CD1 ILE E 115 −20.108 2.486 −10.414 1.00 52.31 CATOM 2909 CG2 ILE E 115 −18.429 0.233 −11.703 1.00 50.04 C ATOM 2910 CILE E 115 −15.698 −0.097 −10.663 1.00 51.45 C ATOM 2911 O ILE E 115−14.888 0.552 −11.342 1.00 51.91 O ATOM 2912 N ASP E 116 −15.713 −1.426−10.604 1.00 55.09 N ATOM 2913 CA ASP E 116 −14.838 −2.269 −11.446 1.0058.10 C ATOM 2914 CB ASP E 116 −14.477 −3.551 −10.704 1.00 57.84 C ATOM2915 CG ASP E 116 −13.320 −3.361 −9.748 1.00 59.39 C ATOM 2916 OD1 ASP E116 −12.283 −2.772 −10.153 1.00 58.51 O ATOM 2917 OD2 ASP E 116 −13.450−3.816 −8.591 1.00 61.50 O ATOM 2918 C ASP E 116 −15.346 −2.612 −12.8621.00 59.18 C ATOM 2919 O ASP E 116 −14.564 −2.484 −13.826 1.00 59.43 OATOM 2920 N PRO E 117 −16.632 −3.068 −12.982 1.00 60.29 N ATOM 2921 CAPRO E 117 −17.292 −3.632 −14.189 1.00 61.09 C ATOM 2922 CB PRO E 117−18.750 −3.133 −14.046 1.00 61.33 C ATOM 2923 CG PRO E 117 −18.991−3.196 −12.535 1.00 60.80 C ATOM 2924 CD PRO E 117 −17.592 −3.089−11.852 1.00 60.62 C ATOM 2925 C PRO E 117 −16.713 −3.318 −15.593 1.0062.20 C ATOM 2926 O PRO E 117 −16.501 −2.150 −15.971 1.00 62.74 O ATOM2927 OXT PRO E 117 −16.466 −4.245 −16.386 1.00 62.43 O ATOM 2928 ZN ZN E502 −12.635 7.037 −4.437 1.00 27.25 ZN ATOM 2929 ZN ZN E 501 −26.60821.029 −5.804 1.00 39.92 ZN ATOM 2930 OH2 HOH W 1 −17.549 40.654 24.3181.00 31.56 ATOM 2931 OH2 HOH W 2 17.362 20.052 −2.479 1.00 25.50 ATOM2932 OH2 HOH W 3 −2.011 29.501 11.491 1.00 30.11 ATOM 2933 OH2 HOH W 4−1.231 11.877 4.344 1.00 33.10 ATOM 2934 OH2 HOH W 5 −15.837 4.131−2.007 1.00 34.35 ATOM 2935 OH2 HOH W 6 −18.878 24.607 32.037 1.00 37.33ATOM 2936 OH2 HOH W 7 −8.008 1.692 −4.434 1.00 36.76 ATOM 2937 OH2 HOH W8 0.580 21.608 13.618 1.00 37.53 ATOM 2938 OH2 HOH W 9 16.380 17.88210.672 1.00 37.87 ATOM 2939 OH2 HOH W 10 −22.130 37.815 21.073 1.0035.89 ATOM 2940 OH2 HOH W 11 4.673 13.758 −32.750 1.00 33.95 ATOM 2941OH2 HOH W 12 −20.499 24.465 5.437 1.00 28.59 ATOM 2942 OH2 HOH W 1323.425 25.428 −2.508 1.00 37.38 ATOM 2943 OH2 HOH W 14 −14.983 15.840−4.699 1.00 46.26 ATOM 2944 OH2 HOH W 15 −10.233 9.257 −27.822 1.0038.63 ATOM 2945 OH2 HOH W 16 −21.192 34.424 12.062 1.00 37.61 ATOM 2946OH2 HOH W 17 0.053 26.141 −3.950 1.00 54.93 ATOM 2947 OH2 HOH W 18−5.394 4.386 9.736 1.00 37.09 ATOM 2948 OH2 HOH W 19 −8.975 14.385−2.075 1.00 37.40 ATOM 2949 OH2 HOH W 20 −11.483 11.732 −4.064 1.0048.02 ATOM 2950 OH2 HOH W 21 8.538 14.250 −15.163 1.00 45.77 ATOM 2951OH2 HOH W 22 −13.507 26.363 33.684 1.00 36.52 ATOM 2952 OH2 HOH W 23−22.909 39.389 25.431 1.00 51.50 ATOM 2953 OH2 HOH W 24 −6.016 34.96215.554 1.00 40.08 ATOM 2954 OH2 HOH W 25 −27.799 20.311 13.356 1.0040.64 ATOM 2955 OH2 HOH W 26 −9.659 40.204 28.277 1.00 50.22 ATOM 2956OH2 HOH W 27 −22.574 19.101 15.450 1.00 47.34 ATOM 2957 OH2 HOH W 28−37.126 26.264 −0.600 1.00 39.56 ATOM 2958 OH2 HOH W 29 −9.898 30.1121.970 1.00 56.19 ATOM 2959 OH2 HOH W 30 14.875 14.573 −3.591 1.00 37.15ATOM 2960 OH2 HOH W 31 −1.553 2.908 9.016 1.00 47.01 ATOM 2961 OH2 HOH W32 −21.032 30.547 7.051 1.00 40.04 ATOM 2962 OH2 HOH W 33 −0.209 7.321−31.105 1.00 38.83 ATOM 2963 OH2 HOH W 34 −9.687 37.554 14.224 1.0043.90 ATOM 2964 OH2 HOH W 35 −22.793 14.964 −8.325 1.00 50.86 ATOM 2965OH2 HOH W 36 −8.615 28.359 −20.387 1.00 40.23 ATOM 2966 OH2 HOH W 37−14.482 27.081 1.103 1.00 48.65 ATOM 2967 OH2 HOH W 38 −21.411 9.115−11.631 1.00 44.01 ATOM 2968 OH2 HOH W 39 −11.464 1.095 −12.508 1.0045.05 ATOM 2969 OH2 HOH W 40 −0.402 15.047 −34.444 1.00 41.68 ATOM 2970OH2 HOH W 41 13.970 29.824 −18.438 1.00 46.66 ATOM 2971 OH2 HOH W 420.010 18.179 −1.761 1.00 44.33 ATOM 2972 OH2 HOH W 43 −24.141 42.09827.887 1.00 62.32 ATOM 2973 OH2 HOH W 44 −28.543 34.801 14.268 1.0048.79 ATOM 2974 OH2 HOH W 45 −19.052 36.669 14.149 1.00 43.38 ATOM 2975OH2 HOH W 46 −21.027 5.982 −0.187 1.00 43.29 ATOM 2976 OH2 HOH W 47−11.461 10.710 26.650 1.00 45.24 ATOM 2977 OH2 HOH W 48 −32.578 9.524−0.486 1.00 62.86 ATOM 2978 OH2 HOH W 49 −25.755 40.650 29.914 1.0048.32 ATOM 2979 OH2 HOH W 50 −1.405 33.346 −4.925 1.00 60.35 ATOM 2980OH2 HOH W 51 −5.133 15.525 3.092 1.00 32.86 ATOM 2981 OH2 HOH W 52−13.645 18.564 32.922 1.00 50.50 ATOM 2982 OH2 HOH W 53 −12.789 9.52130.610 1.00 53.37 ATOM 2983 OH2 HOH W 54 −9.573 17.794 28.093 1.00 49.45ATOM 2984 OH2 HOH W 55 −12.428 24.883 −14.429 1.00 43.17 ATOM 2985 OH2HOH W 56 −27.927 17.852 13.258 1.00 49.70 ATOM 2986 OH2 HOH W 57 2.3888.886 18.777 1.00 45.10 ATOM 2987 OH2 HOH W 58 −12.077 0.367 −3.463 1.0044.30 ATOM 2988 OW0 HOH W 59 1.704 8.508 14.181 1.00 30.60 ATOM 2989 OW0HOH W 60 −7.056 24.808 −1.087 1.00 33.17 ATOM 2990 OW0 HOH W 61 −12.39210.737 −1.805 1.00 34.81 ATOM 2991 OW0 HOH W 62 −2.525 5.036 5.866 1.0036.96 ATOM 2992 OW0 HOH W 63 −12.292 41.162 28.775 1.00 28.15 ATOM 2993OW0 HOH W 64 −7.563 19.859 7.620 1.00 29.26 ATOM 2994 OW0 HOH W 65−15.842 2.676 −14.366 1.00 53.47 ATOM 2995 OW0 HOH W 66 −31.515 20.265−4.155 1.00 35.35 ATOM 2996 OW0 HOH W 67 −3.936 8.455 −26.236 1.00 32.60ATOM 2997 OW0 HOH W 68 −11.026 3.554 −0.830 1.00 40.04 ATOM 2998 OW0 HOHW 69 −19.858 20.494 4.314 1.00 31.44 ATOM 2999 OW0 HOH W 70 8.620 14.453−26.618 1.00 35.55 ATOM 3000 OW0 HOH W 71 −2.280 13.892 6.137 1.00 38.09ATOM 3001 OW0 HOH W 72 4.718 30.472 −24.432 1.00 38.03 ATOM 3002 OW0 HOHW 73 −5.982 20.628 −1.464 1.00 46.93 ATOM 3003 OW0 HOH W 74 3.340 20.9024.854 1.00 37.94 ATOM 3004 OW0 HOH W 75 18.667 21.796 −0.422 1.00 35.98ATOM 3005 OW0 HOH W 76 −9.114 7.695 8.920 1.00 46.41 ATOM 3006 OW0 HOH W77 −2.725 9.410 −24.189 1.00 35.50 ATOM 3007 OW0 HOH W 78 26.980 18.89912.829 1.00 31.81 ATOM 3008 OW0 HOH W 79 17.646 21.683 3.437 1.00 31.91ATOM 3009 OW0 HOH W 80 −8.571 17.509 −24.553 1.00 34.33 ATOM 3010 OW0HOH W 81 −7.652 32.985 8.726 1.00 43.98 ATOM 3011 OW0 HOH W 82 −2.6255.632 −10.150 1.00 36.97 ATOM 3012 OW0 HOH W 83 −12.028 32.276 7.2271.00 39.35 ATOM 3013 OW0 HOH W 84 −33.711 27.130 −3.174 1.00 42.56 ATOM3014 OW0 HOH W 85 −17.611 17.995 17.184 1.00 34.50 ATOM 3015 OW0 HOH W86 −19.109 18.971 27.592 1.00 35.69 ATOM 3016 OW0 HOH W 87 −21.99122.413 5.160 1.00 39.27 ATOM 3017 OW0 HOH W 88 13.659 19.242 −8.046 1.0047.60 ATOM 3018 OW0 HOH W 89 −10.339 18.565 25.687 1.00 42.43 ATOM 3019OW0 HOH W 90 1.970 26.030 6.048 1.00 40.39 ATOM 3020 OW0 HOH W 91 −8.76521.673 0.433 1.00 37.72 ATOM 3021 OW0 HOH W 92 −20.850 26.325 2.908 1.0056.35 ATOM 3022 OW0 HOH W 93 −12.366 9.191 20.494 1.00 34.84 ATOM 3023OW0 HOH W 94 −9.896 37.447 29.444 1.00 34.76 ATOM 3024 OW0 HOH W 95−17.552 18.919 −5.164 1.00 41.85 ATOM 3025 OW0 HOH W 96 6.232 22.128−7.201 1.00 41.21 ATOM 3026 OW0 HOH W 97 −6.797 16.849 0.240 1.00 36.86ATOM 3027 OW0 HOH W 98 1.161 18.227 −5.047 1.00 57.06 ATOM 3028 OW0 HOHW 99 2.288 6.066 6.745 1.00 37.06 ATOM 3029 OW0 HOH W 100 −29.295 32.63511.013 1.00 43.96 ATOM 3030 OW0 HOH W 101 −28.464 25.424 7.690 1.0045.49 ATOM 3031 OW0 HOH W 102 −30.152 13.612 −9.680 1.00 43.80 ATOM 3032OW0 HOH W 103 −1.599 6.868 17.329 1.00 42.18 ATOM 3033 OW0 HOH W 104−1.887 24.290 18.531 1.00 44.13 ATOM 3034 OW0 HOH W 105 27.796 19.4553.634 1.00 48.46 ATOM 3035 OW0 HOH W 106 −8.030 10.167 −31.332 1.0048.25 ATOM 3036 OW0 HOH W 107 −2.985 30.050 15.427 1.00 49.05 ATOM 3037OW0 HOH W 108 −1.504 32.061 −21.190 1.00 44.44 ATOM 3038 OW0 HOH W 1096.204 30.000 −16.933 1.00 42.31 ATOM 3039 OW0 HOH W 110 −4.122 20.60523.054 1.00 41.35 ATOM 3040 OW0 HOH W 111 −9.885 40.341 21.208 1.0043.88 ATOM 3041 OW0 HOH W 112 −20.863 15.617 19.646 1.00 52.25 ATOM 3042OW0 HOH W 113 −27.560 21.675 7.325 1.00 36.97 ATOM 3043 OW0 HOH W 114−13.970 38.207 15.196 1.00 36.20 ATOM 3044 OW0 HOH W 115 −10.257 8.67016.396 1.00 44.34 ATOM 3045 OW0 HOH W 116 −26.779 32.379 17.536 1.0046.46 ATOM 3046 OW0 HOH W 117 14.378 29.066 −14.762 1.00 43.06 ATOM 3047OW0 HOH W 118 −19.826 37.668 18.886 1.00 43.88 ATOM 3048 OW0 HOH W 1197.366 26.176 −46.829 1.00 49.36 ATOM 3049 OW0 HOH W 120 −29.626 18.95111.431 1.00 43.10 ATOM 3050 OW0 HOH W 121 −14.313 21.458 −18.725 1.0040.54 ATOM 3051 OW0 HOH W 122 −0.759 26.600 1.740 1.00 45.86 ATOM 3052OW0 HOH W 123 −2.111 2.918 −16.154 1.00 46.67 ATOM 3053 OW0 HOH W 1243.331 26.748 −37.297 1.00 48.14 ATOM 3054 OW0 HOH W 125 −2.436 28.999−11.573 1.00 46.74 ATOM 3055 OW0 HOH W 126 10.219 29.479 4.241 1.0056.66 ATOM 3056 OW0 HOH W 127 8.822 19.046 9.037 1.00 46.32 ATOM 3057OW0 HOH W 128 −2.874 16.046 4.626 1.00 37.70 ATOM 3058 OW0 HOH W 129−0.279 3.806 5.506 1.00 52.87 ATOM 3059 OW0 HOH W 130 −32.360 19.4131.195 1.00 50.24 ATOM 3060 OW0 HOH W 131 −6.511 17.061 −7.831 1.00 39.09ATOM 3061 OW0 HOH W 132 2.417 23.144 8.408 1.00 44.56 ATOM 3062 OW0 HOHW 133 −16.608 10.384 −12.085 1.00 45.07 ATOM 3063 OW0 HOH W 134 −2.84629.191 3.912 1.00 46.72 ATOM 3064 OW0 HOH W 135 −17.527 21.749 4.4201.00 43.90 ATOM 3065 OW0 HOH W 136 −23.992 22.344 21.494 1.00 41.44 ATOM3066 OW0 HOH W 137 −23.795 27.206 3.547 1.00 54.65 ATOM 3067 OW0 HOH W138 −29.116 14.677 5.068 1.00 51.65 ATOM 3068 OW0 HOH W 139 9.313 19.837−4.271 1.00 55.48 ATOM 3069 OW0 HOH W 140 −15.044 19.642 5.067 1.0042.06 ATOM 3070 OW0 HOH W 141 3.974 1.933 15.902 1.00 52.22 ATOM 3071OW0 HOH W 142 0.091 17.275 4.399 1.00 49.56 ATOM 3072 OW0 HOH W 143−25.537 21.936 14.509 1.00 42.90 ATOM 3073 OW0 HOH W 144 −15.697 22.1352.544 1.00 53.67 ATOM 3074 OW0 HOH W 145 −16.772 39.732 17.788 1.0046.17 ATOM 3075 OW0 HOH W 146 −22.834 23.263 26.427 1.00 44.02 ATOM 3076OW0 HOH W 147 −4.433 30.459 1.897 1.00 54.37 ATOM 3077 OW0 HOH W 14810.805 29.216 −12.444 1.00 46.47 ATOM 3078 OW0 HOH W 149 9.875 15.248−22.074 1.00 39.59 ATOM 3079 OW0 HOH W 150 19.274 21.111 10.902 1.0045.24 ATOM 3080 OW0 HOH W 151 −23.788 22.513 −8.738 1.00 50.90 ATOM 3081OW0 HOH W 152 −18.012 12.403 12.283 1.00 58.78 ATOM 3082 OW0 HOH W 153−23.602 19.922 19.962 1.00 46.19 ATOM 3083 OW0 HOH W 154 19.294 22.35813.809 1.00 47.46 ATOM 3084 OW0 HOH W 155 −16.570 11.359 31.299 1.0048.30 ATOM 3085 OW0 HOH W 156 −10.846 16.772 31.754 1.00 51.00 ATOM 3086OW0 HOH W 157 −6.781 8.331 −29.531 1.00 48.71 ATOM 3087 OW0 HOH W 158−25.361 37.429 21.866 1.00 53.58 ATOM 3088 OW0 HOH W 159 −25.833 29.68621.358 1.00 50.75 ATOM 3089 OW0 HOH W 160 −47.219 5.581 −4.792 1.0056.63 ATOM 3090 OW0 HOH W 161 6.673 27.621 −10.556 1.00 44.41 ATOM 3091OW0 HOH W 162 0.676 23.720 14.657 1.00 45.33 ATOM 3092 OW0 HOH W 163−17.977 1.385 −4.066 1.00 49.80 ATOM 3093 OW0 HOH W 164 6.273 19.800−5.128 1.00 41.05 ATOM 3094 OW0 HOH W 165 1.774 1.455 12.183 1.00 53.13ATOM 3095 OW0 HOH W 166 −47.850 5.153 0.253 1.00 54.28 ATOM 3096 OW0 HOHW 167 0.571 0.928 −8.183 1.00 57.03 ATOM 3097 OW0 HOH W 168 −15.65741.281 19.809 1.00 33.76 ATOM 3098 OW0 HOH W 169 −1.350 19.580 18.8941.00 48.90 ATOM 3099 OW0 HOH W 170 −22.822 18.718 −8.056 1.00 46.46 ATOM3100 OW0 HOH W 171 −27.476 27.793 21.291 1.00 44.42 ATOM 3101 OW0 HOH W172 −13.995 8.378 13.827 1.00 46.07 ATOM 3102 OW0 HOH W 173 1.334 4.996−4.827 1.00 43.01 ATOM 3103 OW0 HOH W 174 6.478 14.054 −35.398 1.0065.54 ATOM 3104 OW0 HOH W 175 −12.962 4.523 −16.881 1.00 54.38 ATOM 3105OW0 HOH W 176 8.991 14.162 −32.740 1.00 48.50 ATOM 3106 OW0 HOH W 17730.119 7.742 6.505 1.00 52.79 ATOM 3107 OW0 HOH W 178 4.020 0.076 −9.8891.00 58.79 ATOM 3108 OW0 HOH W 179 1.144 5.559 −8.474 1.00 65.45 ATOM3109 OW0 HOH W 180 2.468 19.016 −2.946 1.00 58.33 ATOM 3110 OW0 HOH W181 8.790 31.553 −20.525 1.00 54.64 ATOM 3111 OW0 HOH W 182 −2.08820.162 20.999 1.00 50.34 ATOM 3112 OW0 HOH W 183 −13.986 18.401 1.8981.00 42.05 ATOM 3113 OW0 HOH W 184 −12.269 28.571 −31.407 1.00 56.39ATOM 3114 OW0 HOH W 185 3.689 19.990 −5.623 1.00 51.48 ATOM 3115 OW0 HOHW 186 −17.974 38.675 31.865 1.00 38.99 ATOM 3116 OW0 HOH W 187 −19.15828.362 36.510 1.00 54.63 ATOM 3117 OW0 HOH W 188 −0.990 2.141 −5.4891.00 52.92 ATOM 3118 OW0 HOH W 189 −16.508 19.586 −9.105 1.00 39.50 ATOM3119 OW0 HOH W 190 −8.651 33.293 29.448 1.00 51.21 ATOM 3120 OW0 HOH W191 −21.074 18.375 −10.228 1.00 59.13 ATOM 3121 OW0 HOH W 192 −6.9612.168 −15.223 1.00 50.82 END

What is claimed is:
 1. A method of prophylaxis of a disease conditioncaused by the influenza A virus comprising administering to a subject inneed thereof a therapeutically effective amount of a live attenuatedinfluenza A virus vaccine comprising a mutated NS1A protein wherein saidmutated NS1A protein comprises one or more mutations at specificresidues in the CPSF30-binding site, a tetramer interface, andcombinations thereof, of the NS1A protein based on the 3D structure ofthe complex formed between NS1A (85-215) and F2F3, wherein said specificresidues are selected from the group consisting of F103, L105, M106,K110, I117, I119, Q121, D125, L144, V180, G183, G184, W187 of SEQ IDNO:
 1. 2. The method of claim 1, wherein the live attenuated influenza Avirus vaccine further comprises one or more mutations in thedsRNA-binding epitope of NS1A.